Topical regional neuro affective therapy with cannabinoid combination products

ABSTRACT

A method of treating a disease state or condition in humans via topical brainstem afferent stimulation therapy via the administration of a cannabinoid drug(s) and a second therapeutically active agent(s) to the back of the neck of a human patient to provide regional neuro-affective therapy is disclosed. In certain preferred embodiments, the cannabinoid drug(s) are not psychoactive or substantially not psychoactive. In certain embodiments, the drugs are incorporated into a pharmaceutically acceptable topical carrier, e.g., a cream. In certain preferred embodiments, the cannabinoid drug(s) comprises cannabidiol.

This application claims priority to U.S. Application No. 62/126,757,filed on Mar. 2, 2015 and U.S. Application No. 62/299,260, filed on Feb.24, 2016; the disclosures of which are hereby incorporated by referenceherein.

FIELD OF THE INVENTION

The invention relates to topical regional neuro-affective therapy (“TRNATHERAPY”) with cannabinoids, such as cannabidiol (CBD). This isaccomplished via administration of effective amounts of these agents onthe back of the neck.

BACKGROUND OF THE INVENTION

The approximate 2½ pound human brain is comprised of the most complexmaterial known to man. The neuron, the primary functional cell of thenervous system, operates on the basis of electrical impulses that resultin the release of neurochemical substances (neurotransmitters) atspecific receptors: dopamine, serotonin, acetylcholine, norepinephrine,gamma-amino butyric acid (GABA), and many others. There are estimated tobe 80-100 billion (10 times the world population) neurons in the averagehuman brain. These neurons, in turn, make 200-300 billion codedconnections with other neurons to accomplish the complex tasks of thehuman body.

The brainstem serves as the vital pathway for relay and processing ofneural impulses flowing continuously between the brain and the rest ofthe body. It is about the size of the thumb and contains the most denseand complicated wiring systems in the human body. In addition to theaxons and dendrites (wires) that carry nerve impulses, the brainstemalso contains critical nuclei that function as electrical generators andrelays. Some of the nuclei are related to cranial nerve function whileothers serve as generators and impulse centers for pain perception, theautonomic system “fight or flight” response, wakefulness and alertness,as well as cardio-respiratory and related autonomic functions.

The endocannabinoid system (ECS) is involved in regulating a variety ofphysiological processes including appetite, pain and pleasure sensation,immune system, mood, and memory. Endocannabinoid receptors in the braininteract with cannabinoids from different sources, including(endocannabinoids (brain derived, e.g., from foods (Omega-3s andOmega-6s); phytocannabinoids (plant derived, e.g., from buds, tinctures,extracts, including tetrahydrocannabinol (THC), cannabidiol (CBD),cannabinol (CBN), etc.); and synthetic cannabinoids (such astetrahydrocannabinol (THC)). Cannabinoids are a diverse class ofchemical compounds that act on cannabinoid receptors on cells andinfluence neurotransmitter release in brain. These receptor proteinsinclude endocannabinoids produced naturally in humans and animals,phytocannabinoids in cannabis and some other plants, and chemicallymanufactured synthetic cannabinoids. PhytocannabinoidΔ9-tetrahydrocannabinol (THC) is the primary psychoactive compound ofcannabis. Cannabidiol (CBD) is another major constituent of the plant,and comprises up to 40% extracts of plant resin. At least 85 differentcannabinoids isolated from cannabis exhibit varied effects.

There is no greater example of a “double-edged sword” in medicaltherapeutics than medical marijuana. While benefits for treatingsymptoms of diverse neurologic and psychiatric conditions have beenknown and practiced by ancient civilizations for thousands of years,marijuana's psychoactive effects have also led to abuse and labeling asa “gateway drug” for more addictive compounds. There is no class oftherapeutic compounds with more controversy and stigma thancannabinoids, active components of the cannabis plant.

The U.S. Government has indicated there is no medical benefit formarijuana and classified it Controlled Substance Category 1, as heroin.It is considered by federal law, illegal to possess or use cannabis andits associated products. However, increasing number of states havechallenged this position and legalized cannabis within their territorieswith varying restrictions and conditions for use. Even then, withinindividual states, such as in Colorado, marijuana laws vary greatly fromcounty to county.

Although defined under U.S. federal law as having no medical use, U.S.Pat. No. 6,630,507 is held by the United States Department of Health andHuman Services, covering use of cannabinoids for treating a wide rangeof diseases. It is directed to a method of treating diseases caused byoxidative stress comprising administering a therapeutically effectiveamount of a cannabinoid (e.g., cannabidiol) that has substantially nobinding to the NMDA receptor to a subject who has a disease caused byoxidative stress.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method oftreatment in humans with topical afferent neural activation therapy viathe regional administration of one or more cannabinoids useful for thetreatment of such diseases or conditions that may be treated via suchtherapy.

It is an object of the present invention to provide a method for thetreatment of seizures; encephalopathy, including lethargy,focus/attentional problems, and cognitive issues: spasticity; weakness;pain, including radiculopathy and neuropathy; numbness; anxiety andother mood disorders; hypertension; Parkinson's disease; insomnia; aswell as any other disease or condition that may be treated with acannabinoid.

It is an object of the present invention to provide a method for thetreatment of seizures; epilepsy; encephalopathy, including lethargy,focus/attentional problems, and cognitive issues; spasticity; weakness(e.g., muscle weakness); pain, including radiculopathy and neuropathy,lower back pain, and fibromyalgia; numbness and/or tingling; anxiety andother mood disorders; hypertension and autonomic dysfunction;Parkinson's disease and tremors; insomnia; Bell's palsy and facial nervedysfunction; glaucoma, AIDS; cancer; PTSD; trigeminal neuralgia;hemi-facial spasms; Autism/Asperger's; attention Deficit Disorder andHyperactivity; social isolation; occipital neuralgia; TMJ dysfunctionrelated symptoms; cognitive problems including memory disturbance;headaches (migraine and tension); peripheral neuropathy; as well asother conditions or disease states mentioned herein or any other diseaseor condition that may be treated with a cannabinoid.

The above objects and others are attained by virtue of the presentinvention, which is directed in part to a method of treating a diseasestate or condition in a human patient via topical regionalneuro-affective (TRNA) or regional neuro-affective (RNA) therapy viaadministration of a drug at the back of the neck region, or the back ofthe neck, e.g., at the hairline (BONATH). The drug is one or morecannabinoids, along with a second therapeutically active agent,administered at the back of the neck at the hairline in close proximityto and under or on the area of skin above the brain stem to provideregional neuro-affective therapy to the human patient.

In certain preferred embodiments, the cannabinoid drug(s) is derivedfrom an endocannabinoid, a phytocannabinoid, a synthetic cannabinoid, ormixtures of any of the foregoing. In certain preferred embodiments, thecannabinoid comprises cannabidiol.

In certain preferred embodiments, the cannabinoid drug mixtureconcentrate includes from about 0 to about 3% tetrahydrocannabinol, fromabout 0 to about 1% tetrahydrocannabinolic acid, from about 20 to about50% cannabidiol, from about 0 to about 1% cannabidiolic acid, and fromabout 0 to about 1% cannabinol, for a total active cannabinoid level offrom about 20% to about 50%, and the remaining cannabinoids aresubstantially therapeutically inactive.

In certain preferred embodiments, the cannabinoid drug(s) areincorporated into a pharmaceutically acceptable topical formulationalong with a second therapeutically active agent (e.g., as describedherein). In certain preferred embodiments, the cannabinoid drug(s) inthe topical pharmaceutical formulation are at a concentration from about0.75% to about 5%, by weight. In certain embodiments, the unit dose ofthe cannabinoid drug(s) includes from about 1 mg to about 200 mgcannabinoid drug(s) and the cannabinoid drug(s) comprise at least 80%cannabidiol. In certain preferred embodiments, a unit dose of thetopical pharmaceutical formulation comprises from about 3 mg to about 50mg cannabidiol.

In certain preferred embodiments, the pharmaceutically acceptabletopical formulation comprises a topical aqueous-based carrier, with anoptional penetration enhancer.

In certain preferred embodiments, the method further comprises applyinga sufficient amount of the topical pharmaceutical formulation to theback of the neck region of the human patient such that the onset of atherapeutic effect occurs in less than about 30 minutes, or in less than15 minutes. The topical pharmaceutical formulation may be administered(applied to the back of the neck region) on a once a day basis, or on atwice a day basis, a three times a day basis, or on a four times a daybasis.

In certain embodiments, the patient is treated for a condition ordisease state selected from the group consisting of seizures,encephalopathy, spasticity, weakness, pain, numbness, anxiety,hypertension, Parkinson's disease, multiple sclerosis, and insomnia. Inother embodiments, wherein the patient is treated for a conditionselected from the group consisting of lethargy, focus/attentionalproblems, and cognitive issues. In other embodiments, the patient istreated for a condition selected from the group consisting ofradiculopathy and neuropathy. In yet other embodiments, the patient istreated for numbness, or a mood disorder.

In certain embodiments, the method further comprises further comprisestopically administering at the back of the neck region (e.g., BONATH)together with, sequentially, or simultaneously but in separateformulations, an additional drug(s) selected from the group consistingof: an anti-epileptic, an anxiolytic, a neuroleptic, an anti-psychotic,an analgesic, an anti-inflammatory, an anti-Parkinson's disease/syndromedrug, a drug for the treatment of dystonia, a drug for the treatment ofspastic conditions, a drug for the treatment of benignessential/familial tremor, a drug for the treatment of tremor related toMS, a drug for the treatment of chronic encepahalopathies, a drug forthe treatment of congenital CNS degeneration conditions/cerebral palsy,a drug for the treatment of cerebellar degeneration syndromes, a drugfor the treatment of neuropathic and/or neurogenic pain, a drug forappetite suppression, a drug for neurodegenerative conditions, a drugfor the treatment of multiple sclerosis, a drug for the treatment ofinsomnia, a drug for the treatment of fatigue, a drug for the treatmentof vertigo, nausea and/or dizziness, a drug for the treatment ofwriter's cramp and restless leg syndrome, other drugs which canbeneficially be added to the treatment in order to provide an additiveor synergistic effect with respect to treating the patient's diseasestate or condition; and a combination of any of the foregoing. Incertain embodiments, the additional drug(s) is a dopamine agonistselected from the group consisting of apomorphine, pramipexole,ropinirole, bromocriptine, cabergoline, pergolide, rotigotine,entacapone, tocapone, seligiline, dopamine, and mixtures of any of theforegoing. In other embodiments, the disease state or condition isParkinson's disease and/or related syndromes/diseases. In otherembodiments, the additional drug(s) is selected from the groupconsisting of the drug is a dopamine agonist, COMT inhibitors, MAO-Binhibitors, and mixtures of any of the foregoing. In other embodiments,the additional drug(s) is an anti-epileptic drug selected from the groupconsisting of Valproic acid, Leviteracetem, Lamotrigene, Topiramate,Pregabalin, Gabapentin, Carbamazepine, Oxcarbazepine, Phenobarbital andother barbiturates, Tiagabine, Retigabine, Lacosamide, Perampanel, andmixtures of any of the foregoing; or the additional drug(s) is ananxiolytic, a neuroleptic and/or an antipsychotic; or the additionaldrug(s) is an analgesic and/or an anti-inflammatory; or the additionaldrug(s) is used in the treatment of neuropathic and/or neurogenic pain;or the additional drug(s) is for multiple sclerosis; or the additionaldrug(s) is for insomnia; or the additional drug(s) is for fatigue; orthe additional drug(s) is for vertigo, nausea and/or dizziness; or theadditional drug(s) is for writer's cramp and restless leg syndrome; orthe additional drug(s) is a tricyclic antidepressant (TCA), atetracyclic antidepressant, or an atypical antipsychotic.

In certain preferred embodiments, the drug is formulated in apharmaceutically acceptable immediate release topical carrier. Incertain preferred embodiments, the topical carrier is aqueous based, andmay be a cream or gel.

In certain preferred embodiments, the method further comprisesformulating the cannabinoid drug(s) in a pharmaceutically acceptableimmediate release aqueous-based carrier. In other embodiments, the thecannabinoid drug(s) is administered in a topical pharmaceuticalformulation comprising liposomes.

In certain preferred embodiments where the cannabinoid drug(s) areadministered in a topical pharmaceutical formulation, the method furthercomprises applying a sufficient amount to the back of the neck region,e.g., BONATH of the human patient such that the onset of clinical effectoccurs in less than about 30 minutes, and in certain preferredembodiments in less than about 15 minutes.

In certain preferred embodiments, the therapeutically effective amountof the cannabinoid drug(s) is applied as a unit dose comprising fromabout 0.25 mg to about 80 mg.

In certain preferred embodiments, the cannabinoid drug(s) isincorporated into a sustained release transdermal delivery system whichis capable of delivering from about 0.25 mg to about 1000 mg of thecannabinoid drug(s) through the skin of a human patient over a 24 hourperiod, the transdermal delivery system being capable of delivering thecannabinoid drug(s) in such amounts for a time period from about 1 toabout 7 days.

In certain embodiments, the cannabinoid drug(s) is administered viaimplantation or injection at the BONATH, or is administered viainjection in an immediate release pharmaceutically acceptable carrierfor injection. In certain embodiments, the cannabinoid drug(s) isadministered via injection or implantation in a controlled releasecarrier to provide a prolonged effect of the cannabinoid drug(s). Incertain embodiments, the cannabinoid drug(s) is administered to create adepot under the skin at the BONATH.

Certain embodiments of the invention are directed to a topicalformulation, comprising a cannabinoid drug(s) in a pharmaceuticallyacceptable aqueous-based carrier, the cannabinoid drug(s) beingincorporated into the carrier in at least one unit dose comprising fromabout 0.25 mg to about 80 mg cannabinoid drug(s). Preferably, whenapplied in a unit dose to the back of the neck of the human patient thetopical formulation provides an onset of clinical effect occurs in lessthan about 30 minutes.

The invention is also directed to a topical formulation, comprising acannabinoid drug in a formulation suitable for administration at theback of the neck at the hairline in close proximity to and under or onthe area of skin above the brain stem of a human patient to provideregional neuro-affective therapy to the patient. The topical formulationmay be prepared as an immediate, controlled or sustained releaseformulation.

The drug formulations useful in the present invention may be in a formselected from a topical formulation (e.g, a cream, ointment or gel); atransdermal device; or an implantable or injectable formulation.

The invention is further directed to the use of a cannabinoid drug inthe preparation of a medicament for providing regional neuro-affectivetherapy to a human patient, wherein the drug is administered at the backof the neck at the hairline in close proximity to and under or on thearea of skin above the brain stem to provide regional neuro-affectivetherapy to the patient.

In certain embodiments, the cannabinoid drug is applied to the posteriorcervical region of the human in order to initiate the brainstem afferentstimulation therapy. Most preferably, the topical formulation or topicaltherapeutic system is applied to the back of the neck, preferably inclose proximity to or on the area of skin above the brain stem.

In other embodiments, the cannabinoid drug is administered viaimplantation or injection at the back of the neck, e.g., on the back ofthe neck at the hairline (BONATH). In such embodiments, the therapy isaccomplished via the availability of the drug(s) at the free nerveendings under the epidermis. In such embodiments, the drug may beincorporated into an implantation device or may be incorporated into acarrier such as a gel or matrix that will provide a prolongedrelease/effect of the cannabinoid drug(s) at the site. The carrier maybe a hydrophilic or hydrophobic material, a colloidal material, and maybe in a state ranging from a viscous liquid to a solid polymeric insert.

Certain embodiments of the invention are directed to a method oftreatment, comprising delivering a cannabinoid drug(s) through regionalneuro-affective therapy by application as a cream/gel or a sustainedrelease patch applied at the back of the neck, or via administrationunder the skin at the back of the neck via an implantable or injectabledrug formulation or device.

In certain embodiments, the method further provides for atherapeutically effective treatment through topical regionalneuro-affective (TRNA) therapy by application of a drug(s) as acream/gel or a sustained release patch applied at the back of the neckwithout the side-effects and the other draw-backs of the currentinjection method.

In certain preferred embodiments, the cannabinoid drug(s) isadministered at the back of the neck (e.g., BONATH) in an immediaterelease topical formulation in a dose comprising from about 0.25 mg toabout 200 mg of the cannabinoid drug(s), and in certain embodiments morepreferably from about 1 to about 50 mg of the cannabinoid drug(s). Incertain preferred embodiments, the cannabinoid drug(s) are in a morepotent form (e.g., crystallized CBD from a herbal source), and the doseis from about 10 mg to about 20 mg. In certain other embodiments, theimmediate release topical formulation includes from about 1 mg to about10 mg cannabidiol, preferably from about 2 mg to about 6 mg cannabidiol,and most preferably about 4 mg cannabidiol.

In certain preferred embodiments, the method of treatment furthercomprises administering the cannabinoid drug(s) to other areas of thespine and/or peripheral nerves in addition to administration on or atthe back of the neck, in order to provide an additive or synergisticeffect and further modulate afferent neural input to the brain to affectefferent outflow for relief of symptoms.

In certain preferred embodiments, the method of treatment furthercomprises topically administering at the back of the neck together with,sequentially, or simultaneously but in separate formulations, one ormore additional active agents (“drugs”) which may be chosen from thefollowing: an anti-epileptic, an anxiolytic, a neuroleptic, ananti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson'sdisease/syndrome drug, a drug for the treatment of dystonia, a drug forthe treatment of spastic conditions, a drug for the treatment of benignessential/familial tremor, a drug for the treatment of tremor related toMS, a drug for the treatment of chronic encepahalopathies, a drug forthe treatment of congenital CNS degeneration conditions/cerebral palsy,a drug for the treatment of cerebellar degeneration syndromes, a drugfor the treatment of neuropathic and/or neurogenic pain, a drug forappetite suppression, a drug for neurodegenerative conditions, a drugfor the treatment of multiple sclerosis, a drug for the treatment ofinsomnia, a drug for the treatment of fatigue, a drug for the treatmentof vertigo, nausea and/or dizziness, a drug for the treatment ofwriter's cramp and restless leg syndrome, and other drugs which canbeneficially be added to the treatment in order to provide an additiveor synergistic effect with respect to treating the patient's diseasestate or condition.

For purposes of the present invention, the term “back of the neck” or“back of the neck region” is intended to encompass the area or regionextending from (behind) one ear to the other ear of the human patientand from the back of the head (i.e., above the neck) to below thehairline at the back of the neck of the human patient.

For purposes of the present invention, a “topical formulation” includes,for example, ointments, creams, lotions, pastes, gels, etc., whichreleases one or more drugs (e.g., cannabinoid drug(s)s) at apredetermined rate over a defined period of time to a defined site ofapplication.

For purposes of the present invention, an “injectable” formulationincludes, for example, an injectable solution, suspension, gel or thelike and may be in immediate release form or may provide a controlled orsustained release of the drug at the site of administration.

For purposes of the present invention, the term “immediate release”means that the cannabinoid drug(s) is administered at the site ofapplication (e.g., the back of the neck) and is available for immediateabsorption at the site of application. In other words, the term“immediate release” is meant to convey in terms of a topical formulationthe fact that there is nothing in the formulation (e.g., a sustainedrelease carrier) that would delay or slow the availability of the drugat the site of application (in contrast to, e.g., a transdermal deviceor patch).

For purposes of the present invention, an “implantable” formulationincludes, for example, a solid, semisolid or liquid drug formulationwhich can be administered at the back of the neck (e.g., BONATH) eithervia injection and/or via surgical implantation. The solid may comprisemicrospheres, microcapsules, pellets, discs, and the like. Theimplantable formulations of the invention may provide a controlled orsustained release of the drug at the site of administration.

For purposes of the present invention, a “transdermal therapeuticsystem” is defined as a drug-containing device (including e.g., patch,disc, etc.) which releases one or more drugs at a predetermined rateover a defined period of time to a defined site of application.

For purposes of the present invention, “transdermal” delivery is thedelivery by passage of a drug through the skin and into the bloodstream(“traditional” transdermal delivery) and is termed “transdermal systemicdrug delivery (TSD therapy).

For purposes of the present invention, the term “topical neuro-affectivetherapy” is synonymous with the more accurately termed topical regionalneuro-affective therapy (or “TRNA therapy”). This term describesimportant aspects of this delivery method: topical, regional (nearbrainstem and cervical spinal cord), and affecting the free nerveendings of the afferent nervous system, thereby not requiring thepresence of drug in the blood, as with systemic therapies which includesthe transdermal patch wherein the skin is used to have drug enter intothe bloodstream through a continuous application patch. In suchsituations, an ionotophoretic electric current generator may be requiredto cause drug entry into blood against a concentration gradient.

For purposes of the present invention “therapeutically effective” or“effective” amount is meant to be a nontoxic but sufficient amount of acannabinoid compound(s) to provide the desired therapeutic effect.

For purposes of the present invention, an “effective” amount of apermeation enhancer as used herein, for example, means an amount thatwill provide the desired increase in skin permeability and,correspondingly, the desired depth of penetration, rate ofadministration, and amount of drug to be delivered.

For purposes of the present invention, the term “delivers” when usedwith respect to the topical formulation or transdermal therapeuticsystem means that the formulation or system provides a mean relativerelease rate or flux of the drug out of the formulation or system andthrough the skin of the patient.

By “predetermined area of skin” is intended a defined area of intactunbroken living skin. In certain embodiments of the present invention,the predetermined area will be in the range of about 1 cm2 to about 100cm2, preferably in the range of about 10 cm2 to about 100 cm2, morepreferably in the range of about 20 cm2 to about 60 cm2. However, itwill be appreciated by those skilled in the art of topical delivery thatthe area of skin through which drug is administered may varysignificantly, depending on the formulation, dose, the application ofthe formulation, and the like.

“Penetration enhancement” or “permeation enhancement” for purposes ofthe present invention relates to an increase in the permeability of skinto a pharmacologically active agent, i.e., so as to increase the rate atwhich the drug permeates through the skin and enters the bloodstream.The enhanced permeation effected through the use of such enhancers canbe observed by measuring the rate of diffusion of drug through animal orhuman skin using a diffusion cell apparatus.

For purposes of the present invention, the “brainstem afferentstimulation therapy region” is defined as the skin region of the headand/or at the frontotemporal region and/or upper posterior cervicalarea. In certain preferred embodiments, the treatment area is the postcervical area in close proximity to the brain stem. Preferably this areais a relatively hairless area of the patient's head and/or neck.

For purposes of the present invention, the drug may be in the form ofthe base, or may be provided as a pharmaceutically acceptable salt(inorganic or organic) or complex. It may be in an optically pure formor a mixture of stereoisomers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional side view of a human showing the relationship ofupper cervical nerves at the back of the neck, to the trigeminal andvagus nerves and brainstem;

FIG. 2 is an EEG showing a baseline EEG of the patient of Example 13;

FIG. 3 is a post-treatment EEG (i.e., after application of a topicalunit dose of cannabinoid drugs) of the patient of Example 13 at 5minutes after the start of therapy; and

FIG. 4 is a post-treatment EEG (i.e., after application of a topicalunit dose of cannabinoid drugs) of the patient of Example 13 at and 8minutes after the start of therapy;

FIG. 5 is a pre-treatment EEG of the patient of Example 14 showing rightfronto-central excessive beta and sharp waves;

FIG. 6 is a post-treatment EEG of the patient of Example 14 showingright fast activity and sharp waves attenuated;

FIG. 7 is a pre-treatment EEG of the patient of Example 15 showingseizure focus.

FIG. 8 is a post-treatment EEG of the patient of Example 15 showingright fast activity and sharp waves attenuated;

FIG. 9 is a pretreatment EEG of the patient of Example 16 showing leftfronto-central seizure focus;

FIG. 10 is a post-treatment EEG of the patient of Example 16 showingattenuated seizure focus;

FIG. 11 is a pretreatment EEG of the patient of Example 17 showingcortical irritability on the left central region c/w potential forseizures;

FIG. 12 is a post-treatment EEG of the patient of Example 17 showingattenuated seizure focus;

FIG. 13 is a post-treatment Brain MRI of the patient of Example 17showing a left thalamic hamartoma.

DETAILED DESCRIPTION

The therapeutically active agents used in the formulations and methodsof the invention comprise cannabinoid drug(s). Cannabinoids are adiverse class of chemical compounds that act on cannabinoid receptors oncells and influence neurotransmitter release in brain. These receptorproteins include endocannabinoids produced naturally in humans andanimals, phytocannabinoids in cannabis and some other plants, andchemically manufactured synthetic cannabinoids. Endo, phyto and/orsynthetic cannabinoids cause neurotransmitter release which results innerve transmission. Phytocannabinoid Δ9-tetrahydrocannabinol (THC), isprimary psychoactive compound of cannabis. Cannabidiol (CBD) is anothermajor constituent of the plant, up to 40% extracts of plant resin.Cannabidiol (CBD) is one of many active cannabinoids in cannabis. Thecannabinoid may be derived from endocannabinoids (derived, e.g., fromfoods (Omega-3s and Omega-6s); phytocannabinoids (plant derived, e.g.,from buds, tinctures, extracts, including tetrahydrocannabinol (THC),cannabidiol (CBD), cannabinol (CBN), etc.); and synthetic cannabinoids(such as tetrahydrocannabinol (THC)). At least 85 different cannabinoidsisolated from cannabis exhibit varied effects. In certain preferredembodiments, the cannabinoid drug(s), or are not psychoactive or aresubstantially not psychoactive (meaning that if included in theformulation, they are not in sufficient amount that a unit dose of theformulation would cause the patient to have a psychoactive effect). Incertain preferred embodiments, as will be explained further below, thecannabinoid drug is actually a mixture of two or more cannabinoids(e.g., CBD and THC together in a CBD:THC ratio that provides atherapeutic effect while substantially not psychoactive or notpsychoactive at all).

The endocannabinoid system (“ECS”) consists of a group of endogenouscannabinoid receptors located in mammalian brain and throughout thecentral and peripheral nervous systems. These entail neuromodulatorylipids and their associated receptors. As the body's “endogenous,”cannabinoid system, ECS is involved in a variety of physiologicalprocesses including neurological functions dealing with pain, mood,memory; and, movement, and sensation. The body's immune function andcell homeostasis is also maintained by ECS. It mediates the psychoactiveeffects of the cannabis (marijuana) plant. Cannabinoids are a diverseclass of compounds that include many of the unique compounds found inmarijuana.

Cannabinoids produce physiological and behavioral effects throughinteraction with specific membrane-bound receptors. Two primaryendocannabinoid receptors have been identified: CB1 and CB2. There ismounting evidence that more endocannabinoid receptors exist. CB1receptors are found predominantly in brain (specifically in basalganglia and limbic system, including hippocampus) and nervous system, aswell as in peripheral organs and tissues. These are acted on by theendocannabinoid binding molecule Anandamide. Of G protein-coupled typereceptors (GPCR) in human brain, cannabinoid receptors are the mostplentiful. CB1 receptors responsible for euphoric and anti-convulsiveeffects of cannabis. CB2 receptors found only in peripheral nervoussystem appear responsible for anti-inflammatory effect such as painrelief. One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG),active at both CB1 and CB2 cannabinoid receptors. Its mimeticphytocannabinoid is cannabidiol (CBD), while that of Anandamide is THC,responsible for psycho-active effects. 2-AG and CBD are involved inregulation of appetite, immune system functions and pain management.

Tetrahydrocannabinol (THC) has been the primary focus of cannabisresearch since 1964, when Raphael Mechoulam isolated and synthesized it.More recently, the synergistic contributions of cannabidiol to cannabispharmacology and analgesia have been scientifically demonstrated. Otherphytocannabinoids, including tetrahydrocannabivarin, cannabigerol andcannabichromene, exert additional effects of therapeutic interest.Innovative conventional plant breeding has yielded cannabis chemotypesexpressing high titres of each component for future study.

Cannabidiol (CBD) is considered the “medical component” of cannabis andhemp. CBD is considered to have a wide scope of medical applications. Itacts as 5-HT1A receptor agonist which may explain its antidepressant,anxiolytic, and neuroprotective effects. Cannabidiol modulates opioidreceptors involved with pain perception. CBD is not psychoactive andrelieves convulsion, inflammation, anxiety, and nausea. It has also beenfound to play a role in preventing short-term memory loss from THC.Antipsychotic effects of cannabidiol represent potential treatment ofschizophrenia. Oral CBD formulation received orphan drug status in US astreatment for Dravet syndrome, an intractable seizure disorder alsoknown as Severe Myoclonic Epilepsy of Infancy (SMEI). Nabiximols, tradename Sativex, is an aerosolized mist for oral administration containing1:1 ratio of CBD and THC approved 2005 in Canada for multiple sclerosisassociated pain. CBD has a greater affinity for CB2 than CB1 receptor.

CBD acts as serotonin (5-HT1A) receptor agonist which may explain itsantidepressant, anxiolytic, and neuroprotective effects. CBD modulatesopioid receptors involved with pain perception. CBD is not psychoactiveand relieves convulsion (seizures), inflammation, anxiety, and nausea.It has been found to play a role in preventing short-term memory lossfrom THC. Antipsychotic effects of cannabidiol represents potentialtreatment of schizophrenia. CBD has a greater affinity for CB2 than CB1receptors.

Strains of cannabis containing higher CBD concentrations did not produceshort-term memory impairment compared to those with similarconcentrations of THC, but lower CBD concentrations. Attenuation ofmemory effects attributed to CBD's function as CB1 antagonist.Transdermal CBD has been shown to be neuroprotective in animals.Antioxidant properties of cannabidiol have been shown to play a role inits neuroprotective and anti-ischemic effects. Animal experimentsindicate CBD may help in treating Parkinson's disease.

It is known to those skilled in the art that studies have suggested thatmany cannabinoid compounds work together to produce a synergy ofeffects. This is known as the ‘entourage effect.” Thus, in certainpreferred embodiments, the formulations of the invention contain morethan one cannabinoid compound, which provide an “entourage effect.”

CBD has anti-psychotic effects which may counteract psychotomimeticeffects of THC, euphoric and hallucinogenic component of cannabis.Reports show CBD safe and well-tolerated alternative treatment forschizophrenia. A double blind trial comparing purified cannabidiol toatypical antipsychotic amisulpride in acute paranoid schizophreniashowed both treatments were associated with significant decrease inpsychotic symptoms after 2 weeks; but cannabidiol was associated withsignificantly fewer side effects. Studies show cannabidiol affectslimbic system, decreasing symptoms of social anxiety and isolation.Cannabidiol has demonstrated antidepressant-like effects in animalmodels of depression.

In certain preferred embodiments, the cannabinoid is not psychoactive,or only mildly psychoactive. Cannabidiol (CBD) is not psychoactive, andtherefore in certain preferred embodiments, the active cannabinoid drugcomprises cannabidiol, or consists essentially of cannabidiol, orconsists of cannabidiol. In other preferred embodiments, cannabidiolcomprises from about 5% to about 99.9% of the total amount ofcannabinoid drug(s) included in the formulations and treatments of thepresent invention. In other preferred embodiments, cannabidiol comprisesabout 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about80%, about 90% or more, or greater than about 95% of the total amount ofcannabinoid drug(s) included in the formulations and treatments of thepresent invention. In certain embodiments, the CBD is derived fromcrystalline powder, such that the powder is about 95% pure CBD orgreater. In other preferred embodiments, cannabidiol comprises at leastabout 20% of the total amount of cannabinoid drug(s) included in theformulations and treatments of the present invention. In otherembodiments, the cannabinoid drug comprises cannabinol (which is onlymildly psychoactive). In certain embodiments, the cannabinoid drug(s)contained in the formulations of the invention is hemp CBD. In otherembodiments, the cannabinoid drug(s) is cannabis-based and comprises aTHC-CBD (and optionally other cannabinoid combinations derived fromcannabis). As CBD and THC have different mechanisms of action, they mayact synergistically, e.g., to control seizures. In such embodiments, thetherapeutic effect may be via the “entourage effect”.

In other embodiments, the drug is a cannabinoid such as anendocannabinoids (derived, e.g., from foods (Omega-3s and Omega-6s); aphytocannabinoid (plant derived, e.g., from buds, tinctures, extracts,including tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol(CBN), etc.); and synthetic cannabinoids (such as tetrahydrocannabinol(THC)), mixtures thereof, and the like. Further representativecannabinoids useful in the present invention include cannabigerol (CBG),cannabichchromene (CBC), cannabicyclol (CBL), tetrahydrocannabivarin(THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV),cannabigerovarin (CBGV), delta-8-tetrahydrocannabinol,delta-9-tetrahydrocannabinol (Dronabinol), cannabigerol monomethyl ether(CBGM), nabilone, rimonabant (SR141716, a selective cannabinoid (CB₁)receptor inverse agonist), JWH-018, JWH-073, CP-55940,dimethylheptylpyran, HU-331, SR 144528 (a selective CB₂ receptoragonist), levonantradol, AM-2201, beta-caryophyllene, lipophilicalkamides (alylamides) which have affinity for the CB₂ receptor, andchemical derivatives of any of the foregoing. In certain embodiments, asynthetic cannabinoid is used. Synthetic cannabinoids encompass avariety of distinct chemical classes: the classical cannabinoidsstructurally related to THC, including the nonclassical cannabinoids(cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles,qualenel8p, and arylsulfonamides, as well as eicosanoids related to theendocannabinoids. Cannabigerol (“CBG”) is non-psychotomimetic but stillimpacts the overall effects and affects of cannabis. CBG acts as aalpha2-adrenergic receptor agonist, 5-HT1A receptor antagonist, CB1receptor antagonist, and also binds to the CB2 receptor. CBC isnon-psychoactive, and exhibits anti-inflammatory and analgesicproperties. Evidence suggests that CBC may play a role inanti-inflammatory and anti-viral effects, may have antidepressanteffects, may promote neurogenesis, and may contribute to the overallanalgesic effects of cannabis. Delta-9-tetrahydrocannabinol (Dronabinol;commercially available in the U.S. under the tradename Marinol) is usedas an appetite stimulant, anti-emetic, and analgesic. Nabilone (Cesamet,Canemes), a synthetic cannabinoid and an analog of Marinol; Rimonabant(SR141716), a selective CB1 receptor inverse agonist once used as ananti-obesity drug under the tradename Acomplia, and was also used forsmoking cessation.

In certain embodiments, the cannabinoid drug(s) is industrial hemp or anon-psychoactive hemp product.

In yet further embodiments, the cannabinoid drug(s) comprises a naturalcannabinoid compound, a synthetic cannabinoid compound, a semi-syntheticcannabinoid compound, or mixtures thereof. Illustrative of suchcompounds are cannabinoids or cannabinoid analogues selected from thegroup consisting of cannabinol, cannabidiol, delta9-tetrahydrocannabinol, delta 8-tetrahydrocannabinol,hydroxy-tetrahydrocannabinol, 11-hydroxy-9-tetrahydrocannabinol,levonantradol, delta 11-tetrahydrocannabinol, tetrahydrocannabivarin,dronabinol, amandamide, nabilone, a natural or synthetic analoguethereof, a natural or synthetic molecule with a basic cannabinoidstructure, and mixtures of any of the foregoing.

In certain embodiments, the cannabinoid drug(s) included in thetreatment and/or formulations of the present invention comprise a ligandthat binds to the CB₁ or the CB₂ receptor.

Cannabis terpenoids (e.g., limonene, myrcene, α-pinene, linalool,β-caryophyllene, caryophyllene oxide, nerolidol and phytol) share aprecursor with phytocannabinoids, and are all 19quale and fragrancecomponents common to human diets that have been designated GenerallyRecognized as Safe by the US Food and Drug Administration and otherregulatory agencies. Terpenoids are quite potent, and affect animal andeven human 19qualene when inhaled from ambient air at serum levels inthe single digits ng·Ml −1. They display unique therapeutic effects thatmay contribute meaningfully to the entourage effects of cannabis-basedmedicinal extracts. Thus, in certain embodiments, the formulations andtreatments of the present invention include an active drug componentwhich comprises both a phytocannabinoid(s) and a terpenoid(s).Phytocannabinoid-terpenoid interactions may produce synergy with respectto treatment of pain, inflammation, depression, anxiety, addiction,epilepsy, cancer, fungal and bacterial infections (includingmethicillin-resistant Staphylococcus aureus).

Administration at the Back of the Neck

The cannabinoid drug formulations of the present invention arepreferably applied at the back of the neck region of the human patient.In its broadest sense, the term “back of the neck” or “back of the neckregion” is intended to encompass the area or region extending from(behind) one ear to the other ear of the human patient and from the backof the head (i.e., above the neck) to below the hairline at the back ofthe neck of the human patient. More preferably, the administration ofthe cannabinoid drug(s) is located more directly at the back of the neckin the area above the cervical nerve roots, C1-C4 (and optionallyincluding C5) such that administration of the cannabinoid drug(s) are inthe area at or above the skin where the afferent components oftrigeminal nerve system, cervical sympathetic nerves, and vagus nerveare located. In certain preferred embodiments, the back of the neck ismore specifically the back of the neck at or around the hairline of thepatient, which is an area more directly above the C1-C4 cervical nerveroots (this area is referred to herein as “BONATH”). It is to beunderstood that application at the back of the neck is not an exact art,and application of part or all of the dose in proximity to the back ofthe neck (e.g., behind the ears or on the skin higher (on the back ofthe head) or lower (below the hairline, and even below the C5 area) thandirectly above the C1-C4 cervical nerve roots will still provide atherapeutically effective dose in accordance with the invention;however, such locations are not optimal and may cause a lessening of thetherapeutic effect or a delay in onset of therapeutic effect. All suchtreatments are considered to fall within the definition of “back of theneck” for purposes of the present invention.

The administration of a cannabinoid drug(s) at the back of the neck is anovel way to deliver cannabinoids. This is believed to be accomplishedby activation of cutaneous afferent pathways through neuro-chemicalreceptors existing on free nerve-endings. The hypothesis of thistherapeutic modality is based on presence of numerous (hundreds ofthousands to millions) of free nerve-endings below the skin surface(stratum corneum) at upper posterior cervical region, the back of theneck or “nuchal” region. There exist at this location, directconnections through cervical nerve roots, C1-C4, and occasionally, C5,to afferent components of trigeminal nerve system, cervical sympatheticnerves, and vagus nerve providing significant input to CNS. At no otherlocation on the human body is such a magnitude of afferent neural inputaccessible through skin nerve-endings than here. Modulated CNS efferentneural outflow in response to afferent activation manifests asimprovement in clinical symptoms of MS and other conditions of brain andspinal cord impairment. By using direct nerve pathways, by-passing bloodflow and avoiding restrictions of “blood-brain-barrier,” onset oftherapeutic time is greatly reduced and systemic side effects areavoided.

The inventor has observed rapid therapeutic onset of action, generally,less than 10 to 15 minutes administration of cannabinoid drug(s) at theback of the neck, with maximal benefit noted well within 30 minutes. Incertain embodiments, a prolonged therapeutic effect has been noted,e.g., about 4 to about 12 hours or more, depending on condition andseverity of the condition being treated.

The peripheral nervous system (PNS) communicates with central nervoussystem (CNS, consisting of brain, brainstem, and spinal cord) throughdorsal root ganglia which reside just outside the spine and act asneural relay areas between PNS and CNS. The human skin has free nerveendings just below the skin surface (stratum corneum), which are theperipheral end components of spinal dorsal root ganglia. As skin and CNSare both derived from the same embryological tissue, neuro-ectoderm,receptors to neurotransmitters and other substances used in neuralcommunication are similarly represented on both free nerve endings andCNS. This makes sense as the skin needs to communicate directly with CNSwith respect to external stimuli. In fact, these receptors are on thecell surface of skin free nerve endings, making them readily accessibleto compounded drug applications to the skin for neural effect, “topicalneuro-affective therapy.” The binding of the topically administeredcannabinoid drug(s) to these receptors results in electrical actionpotential generation and propagation to CNS, causing therapeutic effectsto occur. As such, these same drug compounds do not need to enter thebloodstream to reach their sites of activity, as it is with systemicdelivery. Systemic side effects and drug activity at sites other thanintended are therefore not present. Further, by working throughestablished neural pathways than through the blood stream, thetherapeutic effects are rapid, generally with 15-30 minutes or less.Many of the current drugs used systemically for peripheral conditionssuch as pain are thought to work by their effect on dorsal root ganglia,modulating neural impulses to brain. With topical neuro-affectivetherapy the effects on dorsal root ganglia are direct and immediate asfree nerve endings are peripheral extensions of the ganglia.

An important aspect of the benefits of “TRNA” or “RNA” therapy in CNSdrug delivery for brainstem related disorders lies in the anatomy of theregion. The free nerve endings with receptors for the neuro-chemicalsdopamine, serotonin, norepinephrine, and others are located just belowthe surface of the skin, easily assessable to drugs compounded in anappropriate dermal penetration enhancing medium and topically applied tothe skin.

To understand the concept of “peripheral neural afferent stimulationtherapy” as it applies to the brainstem and how topical drug delivery tothe back of the neck works requires a review of the neuro-anatomy andthe neuro-physiology of the region. As indicated above, this area of thenervous system is very complicated, compact and highly inter-active andinter-related.

The Trigeminal Nerve System is a component of the brainstem whichcoordinates pain input from the face, head, and the back of the neck. Assuch, it intimately influences the production of other symptomsassociated with syndromes attributed to dysfunction within thetrigeminal complex. These include the photophobia, phonophobia, nausea,anxiety, allodynia, and other focal sensory symptoms which may accompanya migraine attack. Similarly, episodes of trigeminal neuralgia (ticdouloreux) frequently involve significant affective (emotional) andvisceral components. Because of proximity and connections to otherstructures in the brainstem, abnormalities of temperature regulation,thirst, alertness, and mood are common. Some of these symptoms may be asequally disabling as the head and face pain.

In addition to receiving pain and sensory (afferent) input from theface, nasal and para-nasal sinuses, the teeth, scalp, the dura of theanterior and middle cranial fossa, the trigeminal system receivessimilar input from the soft tissues of the posterior cervical region.The free nerve endings in the back of the neck are just below thesurface of the skin, easily accessible to topically delivered drugsformulated in an appropriate dermal penetration enhancing compoundingmedium. The free nerve endings, via the small un-myelinated andmyelinated “C-fibers” (pain fibers) carry pain impulses through afferentsensory nerves back to the Trigeminal Nucleus Caudalis (TNC). TNC is thepain processing center extending from the pons through the entire extentof the brainstem to the upper cervical spinal cord. After synapsing atthe thalamus, pain impulses from TNC travel to the somatosensory cortex,where pain is perceived.

As providing important afferent input to the brain, the trigeminalsystem also receives afferent input from the rest of the body. Afferentinput is defined as any neural impulses coming back to the brain fromthe body. As such it provides information to the brain for processingand interpretation: pain, sensation, autonomic functions. Efferentoutput, on the other hand, consists of impulses originating in thecentral nervous system (brain, brainstem, and spinal cord) flowing tothe body for function: movement, response, action.

FIG. 1 is a sectional side view of a human showing the relationship ofupper cervical nerves at the back of the neck, to the trigeminal andvagus nerves and brainstem. The vagus nerve includes both efferent andafferent fibers and is attached to the lower brainstem (medullaoblongata) via 8-10 radicles. The afferent fibers arise in the jugularand the nodose vagus ganglia. The somatic afferent fibers terminate inthe nucleus of the trigemino-spinal tract (TNC). Both the jugular andthe nodose ganglia are connected with the superior cervical sympatheticgangion through inter-communicating rami. The superior cervicalsympathetic ganglion is located between the internal carotid artery andthe jugular vein on the ventral aspects of the transverse processes ofthe 2^(nd), 3^(rd), and the 4^(th) cervical vertebrae. It is the largestof the sympathetic trunk ganglia.

Sympathetic roots arising from the ganglion join the 1^(st) and the2^(nd) cervical nerves; frequently the 3^(rd), and occasionally, the4^(th). In addition to nerve fibers which extend rostrally from thesuperior cervical sympathetic ganglion, the sympathetic innervation ofthe head includes fibers which join the plexi on the common carotid andthe vertebrtal arteries. The one on the vertebral artery is continuouswith the plexus on the basilar artery. Rami derived from the internalcarotid plexus join the trigeminal nerve and the cavernous plexus inaddition to the other structures such as the abducens and deep petrosalnerves. From the cavernous plexus, located in the middle cranial fossa,sympathetic fibers join the oculomotor, trochlear, and the ophthalmicnerves. Fibers from the plexus also accompany blood vessels into thehypophysis. The spheno-palatine gangion, located in the pterygo-palatinefossa, receives sympathetic fibers from the face with rami distributedto the mucous membranes of the nares, mouth, the pharynx, and someorbital structures.

From the above, it is clear that cervical nerve function is intimatelyrelated to vagal afferents and afferents from the face, head, and thedura of cranial fossae associated with migraine and other head and facepain syndromes.

It has been long reported that vagal nerve stimulation (VNS) in the neckdown-regulates abnormal discharges from epileptic foci and treatsseizures. VNS is now approved as adjunct to medical therapy in certainforms of intractable epilepsy. It is also of benefit in severedepression resistant to traditional drug therapy. Studies with VNS inmigraine, anxiety, and fibromyalgia have been underway and have shownpreliminary promise in benefit. The mechanism of action appears to bethe down-regulation of hyper-excitable, dysfunctional neuronal systemsby increased inhibitory input to brainstem and associated connectionsthrough stimulation of the afferent system. Afferent stimulation, byfeed-back through TNC, causes reduction in efferent output from thebrainstem, resulting in resolution of clinical symptoms throughdown-regulation of hyper-active neuronal structures.

In the same way the electrical stimulation of VNS accomplishes itseffect on the brainstem, topical drug therapy to the posterior cervicalregion, in close proximity to the brainstem and its afferent inputs, istheorized to provide effect for the conditions mentioned above.

It is hypothesized that benefits of the present method of topical drugdelivery of central nervous system (CNS) active drugs lies in the factthat drug concentration gradients and blood flow factors are un-involvedin the therapeutic process. In contrast, the proposed delivery operatesthrough direct nerve connections between skin peripheral nerves at theback of the neck, for example at the hairline (BONATH) and brainstemstructures. Active drug compounded in an appropriate “dermal penetrationenhancing” medium topically applied to the skin at the back of neck haseffect on the free nerve endings of peripheral nerves locatedimmediately below the skin surface. Receptors to dopamine, serotonin,norepinephrine, and other neuro-transmitters/neuro-chemicals involvedwith neural transmission are located on these free nerve endings.Therefore, topically applied drug has near immediate therapeutic effectas direct neural impulses are involved—the concept of brainstem afferentstimulation through topical regional neuro-affective (TRNA) therapy. Allprior art and methods of drug delivery to the CNS have involved bloodflow and therapeutic drug blood level requirements. The inventive methoddoes not require such, which are the source of undesirable systemic andCNS side-effects. The present drug delivery process operates on theprinciple of an electrical capacitor whereas the prior relied on thosefluid dynamics and reservoir principles.

The factors which determine the success of TRNA therapy include: thedrug being considered, the compounding substance (surfactant/dermalpenetration enhancer), the disease process, and the location ofapplication. The free nerve endings in the skin at the back of the neckare important components of the cervical nerves with rich connections tothe trigeminal, vagal, and sympathetic systems communicating withbrainstem structures and other components of the central nervous system.These are the areas pain and other symptoms related to neuro-chemicalrelease are processed and perceived.

The skin at the upper part of the back of the neck, at the hairline, isinnervated by (supplied by nerves) the cervical nerve roots C1-3 thatare also part of the Trigeminal Nerve system of the brainstem. Thesecervical nerves (the wires) have their cell bodies (their generators)within the Nucleus Caudalis (Spinal Nucleus) of the Trigeminal Nerve inthe cervical spinal cord and the brainstem. Accordingly, they havedirect neural connections with brainstem processing areas. At the sametime, the peripheral nerve receptor sites for these nerves, the freenerve endings, reside under the skin surface at the back of the neck.The nerves in the soft tissues of the back of the neck, representing theC1, C2, and C3 segments of the cervical spinal cord are unique in thatthey have intimate connections with pathways directly affectingbrainstem and autonomic system function. There are direct connectionswith the Trigeminal Nerve system of the brainstem which provides forpain and other sensory input and interpretation from the head, face,sinus cavities, the dural covering of the brain, and the back of theneck. There are also connections with the vagus nerve and thesympathetic nervous system through the sympathetic ganglia. It isthrough these connections, which are nowhere else in the body asinter-related or at such close proximity to the surface of the humanskin, that the potential for the delivery of CNS acting drugs throughthe skin at the back of the neck (BONATH) is realized. Finally, skin isembryologically derived from neuro-ectoderm which is also responsiblefor the formation of the brain and other aspects of the CNS. Thus, thenerves in the human skin have a particularly direct relationship withthese structures. This provides for the efficacy noted with TRN/back ofthe neck therapy. At the same time, systemic and other CNS side-effectsare reduced or avoided. Thus, drugs topically applied to the skin inthis region have ready access to brainstem and other CNS structureswithout the requirement of drug in the bloodstream reaching targetsites.

In addition to the upper cervical nerves having direct relation to theTrigeminal Nerve System, they also contribute to the CervicalSympathetic Ganglia and the Vagal Nerve Systems through directconnections. These latter two systems provide some of the mostsignificant afferent feed-back to the brainstem and other portions ofthe CNS from the rest of the body. This allows for additional brainstemafferent stimulation potential through TRNA therapy at the back of theneck. Although skin at other areas of the face and head have eventualneural feed-back to the brainstem, the intimate connections to afferentfeed-back systems are lacking.

The question arises then: does TRNA therapy work with drug applicationto the forehead, face, or other regions of the head. The answer isperhaps—in some disease states such as migraine and face pain; but notas effective and efficient as at the back of the neck or at the back ofthe neck at the hairline (BONATH). Free nerve endings are also presentat these other locations but the distance back to involved brainstemstructures is greater and there is not the added advantage of richafferent neural connections to the trigeminal, vagal, and sympatheticnerve systems that are associated with the posterior cervical region.

TRNA therapy at the back of the neck or at the BONATH delivery differsfrom traditional therapy (whether oral, injection, nasal spray,inhalation, or rectal) in that it has no reliance on the systemic orcerebral blood flow. Nor does it require therapeutic blood levels ofdrug. These latter factors are responsible for systemic and CNSside-effects as drug is delivered to areas not intended to be affectedin the therapeutic process. Transdermal systemic delivery by patch,although similarly applied to the skin as in TRNA therapy, differssignificantly in its reliance on a drug concentration gradient forabsorption into the systemic capillary and venous blood. TRNA therapy isunaffected by dermal vessels or systemic blood flow. It relies solely onthe function of the free nerve endings of cutaneous nerves and theirconnections at the point of application of compounded drug.

“Traditional” transdermal drug delivery by patch and TRNA are both“transdermal” in that in both, drug penetrates the skin (epidermis) foreventual clinical effect. The difference lies in the fact that in“traditional” transdermal patch therapy, drug enters the systemiccirculation through a concentration gradient and establishes atherapeutic drug blood level. Although measuring a blood level givesassurance drug is being taken or delivered systemically, allowing forchecking compliance, it is also the source of undesirable side-effectsand drug interactions. Of necessity, with systemic transdermal patchtherapy, drug applied to the skin surface must be absorbed through thesmall vessels in the dermis for eventual presence in the systemic venousblood for measurement of drug level. With TRNA therapy, the cannabinoiddrug(s) need only be available at the free nerve endings under theepidermis. No concentration gradients or systemic blood levels arenecessary. Drug delivery is unaffected by cardiac output or cerebralblood flow factors. Of significance, persons afflicted with Parkinson'sdisease are typically elderly with concomitant cardiac and cerebralvascular disease.

Thus, in certain embodiments, the methods and formulations of theinvention deliver an amount of drug (e.g., cannabinoid drug(s)) in theTRNA therapy that would provide sub-therapeutic plasma levels ifadministered orally, but which is therapeutically effective whenadministered via TRNA therapy at the back of the neck or at the BONATH.

It is hypothesized by the inventor that a principal reason TRNA therapyis rapid in the onset of clinical effect (e.g., less than about 10-15minutes) for is that it operates through an “electro-chemical” process.Active drug compounded in an appropriate dermal penetration enhancingmedium acts at free nerve endings, changing the neurochemistry ofreceptors at the neural synapse: apomorphine (dopamine andnorepinephrine agonist), increasing dopamine and norepinephrine levelsand improving neural transmission. After a point of receptorstimulation, neural (electrical) impulses are generated back to neuronalcell bodies residing in the spinal cord and brainstem: “afferentfeed-back”. The nervous system functions through neurons generatingelectrical impulses and the release of neurochemicals/neuro-transmitters(serotonin, norepinephrine, dopamine, and acetylcholine, being the majorones) at neural receptor sites called “synaptic clefts”. Accordingly,the process in TRNA therapy may be considered analogous to an electricalcapacitor discharging to perform a function, such as turning on a lightswitch. Viewed from this perspective, the rapid onset of clinical effectobserved in TRNA therapy makes sense.

Alternatively, transdermal systemic patch delivery operates on theprinciples of chemical gradients and fluid dynamics. These processeshave variability and inherent idiosyncrasies, fluctuating heart functionas a pump for blood flow being one. Thus, despite the advantage ofmeasurable drug levels, a more circuitous route with slower clinicaleffect is observed. This makes systemic transdermal patch deliveryinappropriate for acute therapy.

Therapeutic Applications

Potential clinical applications of cannabinoids applied at the back ofthe neck in accordance with the present invention include the following:seizures; epilepsy; encephalopathy, including lethargy,focus/attentional problems, and cognitive issues; spasticity; weakness(e.g., muscle weakness); pain, including radiculopathy and neuropathy,lower back pain, and fibromyalgia; neuropathic pain; numbness and/ortingling; anxiety and other mood disorders; hypertension and autonomicdysfunction; Parkinson's disease and tremors, including EssentialTremor; insomnia; Bell's palsy and facial nerve dysfunction; glaucoma(marijuana is known to reduce pressure in the eye); multiple sclerosis(an extract that relieves pain and muscle spasms in MS patients has beenapproved in Europe and Canada, though not in the U.S. Nabiximols, tradename Sativex, an aerosolized mist for oral administration containing 1:1ratio of CBD and THC)), AIDS (one of the FDA-approved synthetic versionsof a substance found in marijuana, (−)-trans-Δ⁹-tetracydocannabinol(generally referred to as dronabinol) helps increase appetite and treatweight loss in patients with the disease); cancer (dronabinol is alsomarketed in the U.S. to treat nausea associated with chemotherapy;researchers have reported CBD's ability to “turn off” the activity ofID1, a gene responsible for metastasis in breast and other types ofcancers, including aggressive triple negative breast cancer; PTSD;trigeminal neuralgia; hemi-facial spasms; Autism/Asperger's; AttentionDeficit Disorder and Hyperactivity; social isolation; occipitalneuralgia; TMJ dysfunction related symptoms; cognitive problemsincluding memory disturbance; headaches (migraine and tension);peripheral neuropathy; Dravet syndrome (an intractable seizure disorderalso known as Severe Myoclonic Epilepsy of Infancy (SMEI)—an oral CBDformulation received orphan drug status in US as treatment for thiscondition); apnea (including central sleep apnea, obstructive sleepapnea syndrome, and mixed apneas (having components of central andobstructive sleep apneas); smoking cessation; arthritis, includingrheumatoid arthritis; depression; emesis; anti-obesity; nausea;vomiting; alcohol use disorders; dystonia; inflammatory bowel syndrome;neuropathic pain associated with post-herpetic neuralgia; diabeticneuropathy; shingles; burns; actinic keratosis; oral cavity sores andulcers; post-episiotomy pain; psoriasis; pruritis; contact dermatitis;eczema; bullous dermatitis herpetiformis; exfoliative dermatitis;mycosis fungoides; pemphigus; severe eryththema multiforme; seborrheicdermatitis; ankylosing spondylitis; psoriatic arthritis; Reiter'ssyndrome; gout; chondrocalcinosis; joint pain; dysmenorrhea;musculoskeletal pain; molymyositis; bursitis; epicondylitis;osteoarthritis; synovitis; pancreatitis; and other disease states andconditions which will be apparent to those skilled in the art.

In certain preferred embodiments, the cannabinoid drug(s) is formulatedin a vehicle that allows for the drug to be immediately absorbable andavailable for the free nerve endings of the trigeminal nervous systemwhich reside under the skin surface at the back of the neck when theformulation is, e.g., applied to the back of the neck of a human patientin the form of a cream, gel or ointment. On the other hand, it iscontemplated in certain embodiments of the invention that the topical orimplantable cannabinoid drug(s) formulation can be administered in theform that provides a prolonged release at the back of the neck, forexample, in the form of a transdermal patch. The uniqueness of thisparticular area of the human anatomy which allows this delivery methodto work. In further embodiments, the cannabinoid drug(s) is applied (i)in a topical form that provides a therapeutically effective dose of thecannabinoid drug(s) immediately absorbable at the site (back of theneck), and (ii) a further therapeutically effective dose(s) in aprolonged or sustained release formulation (e.g., a transdermal patch orcontained in liposomes) that releases the cannabinoid drug(s) over timesuch that the cannabinoid drug(s) is absorbed at the back of the neck intherapeutically effective amounts over a span of multiple dosage timeintervals (e.g., 1-7 days).

A unit dose of the topical formulation(s) of cannabinoid drug(s) used inaccordance with the present invention preferably includes from about 1mg to about 200 mg cannabinoid drug(s), based on the cannabinoid drugcomprising at least 80% cannabidiol, in certain preferred embodiments atleast 90% cannabidiol, and in certain further preferred embodiments atleast 95% cannabidiol. In certain preferred embodiments, the amount ofpsychoactive cannabinoid drug(s) present in the topical formulations ofthe present invention is less than 20%, more preferably less than 10% orless than 5% of the total active cannabinoids in the topicalformulation.

A representative cannabinoid drug mixture concentrate may include withrespect to total active cannabinoids, for example, from about 0 to about3% tetrahydrocannabinol, from about 0 to about 1% tetrahydrocannabinolicacid, from about 20 to about 50% cannabidiol, from about 0 to about 1%cannabidiolic acid, and from about 0 to about 1% cannabinol, for a totalactive cannabinoid level of from about 20% to about 50%. A particularcannabinoid concentrate useful in the formulations of the presentinvention may include, e.g., about 0.84% tetrahydrocannabinol, about0.23% tetrahydrocannabinolic acid, about 26.41% cannabidiol, about 0%cannabidiolic acid, and about 0.09% cannabinol, for a total activecannabinoid level of about 27.58%, as detected using full spectrumcannabinoid profiling and analysis utilizing High Performance LiquidChromatography (HPLC/UV), and is commercially available from CannaVest.Such a cannabinoid drug mixture may provide the afore-mentionedentourage effect.

In certain embodiments, the topical cannabinoid formulation of thepresent invention is administered at the back of the neck on the humanpatient and a therapeutic effect is preferably provided within about 45minutes, preferably within about 30 minutes, or 25 minutes, or 20minutes, or 15 minutes, or 10 minutes after the administration. Incertain preferred embodiments, a therapeutic effect is noticed withinabout 10 to about 15 minutes after the administration (e.g., applicationof the topical formulation to the back of the neck).

In certain embodiments, the topical cannabinoid formulation isadministered on an “as needed” basis. In other embodiments, the topicalcannabinoid formulation is administered on a once a day basis, or on atwice a day basis, or on a three times a day basis, or on a four times aday basis.

In certain preferred embodiments, a unit dose of the topical cannabinoiddrug(s) formulation provides a cannabinoid (e.g., CBD) dose from about0.1 mg to about 200 mg, and in certain embodiments more preferably fromabout 3 mg to about 50 mg or from about 7.5 mg to about 30 mg. This maybe administered in a topical cream, ointment, gel or the like. Forexample, the topical formulation may be administered as a unit dose inan amount from about 0.5 g to about 1 g at a cannabinoid (e.g., CBD)concentration from about 0.1% to about 5% (or more).

Combination Therapy

In certain preferred embodiments of the invention, the cannabinoid(s) isadministered together with (e.g., in the same formulation), orsimultaneously (but separately) or sequentially with an additionalactive agent(s) (“drug(s)”) suitable for treating the patient's diseasestate or condition. Classes of drugs which would be suitable as anadditional active agent(s) include, but are not limited to:

-   1. Anti-Epileptic drugs: Examples of a second therapeutic agent(s)    include Valproic acid (Depacon®/Depakot®e), Leviteracetem (Keppra®),    Lamotrigene (Lamictal®), Topiramate (Topamax®), Pregabalin    (Lyrica®), Gabapentin (Neurontin®), Carbamazepine (Tegretol®),    Oxcarbazepine (Trileptal®), Phenobarbital and other barbiturates,    Tiagabine (Gabatril®), Retigabine™ (Valeant Pharmaceuticals),    Lacosamide® (Schwarz Biosciences), and Perampanel® (Eisai) are in    development as anti-epileptics and neuromodulators for other    associated neurological, pain, and psychiatric conditions.-   2. Anxiolytic drugs: Benzodiazepines: Examples of a second    therapeutic agent(s) include lorazepam (Ativan®), diazepam    (Valium®), clonazepam (Klonopin®), chlordiazepoxide (Librium®), and    alprazolam (Xanax®).-   3. Neuroleptics/Anti-Psychotic drugs: Examples of a second    therapeutic agent(s) include chlorpromazine (Thorazine®),    haloperidol (Haldol®), risperidone (Risperdal®), olanzapine    (Zyprexa®) and quetiapine (Seroquel®).-   4. Analgesics/Anti-Inflammatory drugs: Examples of a second    therapeutic agent(s) include prednisone, solumedrol, and other    steroids, naproxen, aspirin, acetaminophen, voltaren, ketoprofen,    ibuprofen, other NSAID's.-   5. Parkinson's Disease/Similar or Related Syndrome (e.g., tremors,    spasticity and spasms, dystonia) drugs: Examples of a second    therapeutic agent(s) include dopamine agonists such as apomorphine.-   6. Dystonia (cervical and otherwise), which sometimes occur in    conjunction with spasmdic torticollis and spastic conditions:    Examples of a second therapeutic agent(s) include dopamine agonists    such as apomorphine.-   7. Benign essential/familial tremor, tremor related to MS, chronic    encepahalopathies such as from stroke or head injuries, congenital    CNS degeneration conditions/cerebral palsy, cerebellar degeneration    syndromes, and spasicity conditions from the above: Examples of a    second therapeutic agent(s) of a second therapeutic agent(s) include    dopamine agonists such as apomorphine.-   8. Neuropathic/Neurogenic pain drugs: Examples of a second    therapeutic agent(s) include carbamazepine, gabapentin, topiramate,    zonisamide, phenytoin, desipramine, amitriptyline, imipramine,    doxepin, protriptyline, pentoxifylline, and hydroxyzine.-   9. Smoking Cessation drugs: Examples of a second therapeutic    agent(s) include drugs such as varenicline.

10. Appetite Suppressant drugs: Examples of a second therapeuticagent(s) include drugs such as Sibutramine.

11. Neurodegenerative Diseases: Examples of a second therapeuticagent(s) include Aricept/donepezil, Exelon/rivastigmine,Reminyl/Razadyne/galantamine, and Namenda/memantine and their naturallyoccurring counterparts, as well as NMDA antagonists.

-   12. Multiple Sclerosis (MS): Examples of a second therapeutic    agent(s) include drugs such as 4-aminopyridine.-   13. Insomnia: Examples of a second therapeutic agent(s) include    drugs such as zolpidem or melatonin.-   14. Fatigue: Examples of a second therapeutic agent(s) include drugs    such as pemoline and Modafinil.-   15. Vertigo, Nausea and/or Dizziness: Examples of a second    therapeutic agent(s) include drugs such as as meclizine,    dimenhydrinate, prochlorperazine, scopolamine and diphenhydramine.-   16. Writer's cramp and restless leg syndrome: Examples of a second    therapeutic agent(s) include dopamine agonists such as apomorphine.-   17. Migraine: examples of a second therapeutic agent(s) include    serotonin agonists, such as sumatriptan; ergot alkaloids such as    ergotamine; skeletal muscle relaxants such as tizanidine; and    combinations of any of the foregoing.-   18. Muscle spasms and spasticity: examples of a second therapeutic    agent(s) include skeletal muscle relaxants such as tizanidine, as a    norepinephrine alpha-adrenergic receptor agonist; 4-amino pyridine,    with agonist and antagonist activities at neurochemical receptor    sites affecting glutamate, dopamine, serotonin function in CNS, as    well as that of other neurotransmitters to improve nerve conduction,    reduce spasticity, and improve neurological function in multiple    sclerosis, MS, stroke; and brain and spinal cord injuries.-   19. Peripherally applied, topical 4-amino pyridine found useful in    diabetic peripheral neuropathy, DPN, and other peripheral    neuropathic conditions.-   20. ADD/ADHD and/or Tourette's syndrome: an example of a second    therapeutic agent(s) would be phentermine.-   21. Anxiety and/or panic attacks and/or mood disorders: an example    of a second therapeutic agent(s) is milnacipran.

In certain embodiments, the additional drug(s) includes a dopamineagonist such as apomorphine (Apokyn®, APO-go®), pramipexole(Mirapexin®), ropinirole (Requip®), bromocriptine (Parlodel®),cabergoline (Cabaser®, Dostinex®), pergolide (Permax®, Celance®)rotigotine (Neupro®), mixtures of any of the foregoing, or otherdopamine agonists known to those skilled in the art. One skilled in theart will appreciate that dopamine agonists other than apomorphine may beused in the formulations and methods of the present invention, and allsuch agents are meant to be encompassed by the term “dopamine agonists.”For example, such drugs include, but are not limited to, carbidopa(Sinemet®), dopamine agonists (Requip®, Rotigotine®, Mirapex®), COMTinhibitors (Entacapone®, Tocapone), rasagiline (Azilect®) (MAOinhibitors) and MAO-B inhibitors (Selegiline (Eldepryl®). In certainpreferred embodiments, the concentration of dopamine agonist included inthe topical unit dose is from about 0.25 mg to about 4 mg, based onapomorphine, or an therapeutically equivalent amount of another dopamineagonist as described herein.

In other embodiments, the additional drug(s) includes an opioid such asmorphine, codeine, dihydrocodeine, hydrocodone, hydromorphone,nicomorphine, oxycodone, oxymorphone, fentanyl, alphamethylfentanyl,alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl,thebaine, oripavine, diacetylmorphine (heroin), phenylpiperidines suchas pethidine (meperidine) and ketobemidone, allylprodine, prodine,propoxyphene, dextropropoxyphene, dextromoramide, bezitramide,piritramide, methadone, dipipanone, levomethadyl Acetate (LAAM),loperamide, diphenoxylate, dezocine, pentazocine, phenazocine,buprenorphine, dihydroetorphine, etorphine, butorphanol, nalbuphine,levorphanol, levomethorphan, lefetamine, meptazinol, tilidine, tramadol,tapentadol, mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is tarpentadol (acentrally acting oral analgesic having two mechanisms of actioncombining mu-opioid receptor agonism and norepinephrine reuptakeinhibition).

In yet other embodiments, the additional drug(s) is a selectivenorepinephrine reuptake inhibitor, such as Atomoxetine (Strattera®),Mazindol (Mazanor®, Sanorex®), Nisoxetine (LY-94939), Reboxetine(Edronax®, Vestra®), Viloxazine (Vivalan®), mixtures thereof, and thelike.

In yet other embodiments, the additional drug(s) is a benzodiazepine,such as lorazepam (Ativan®), diazepam (Valium®), clonazepam (Klonopin®),chlordiazepoxide (Librium®), alprazolam (Xanax®), temazepam (Restoril®),mixtures thereof, and the like. In other embodiments, the drug is aneuroleptic or psychotropic such as chlorpromazine (Thorazine®),haloperidol (Haldol®), risperidone (Risperdal®), olanzapine (Zyprexa®)and quetiapine (Seroque®).

In other embodiments, the additional drug(s) is an agent that treatsdepression and/or anxiety, for example, selective serotonin reuptakeinhibitors (SSRIs) such as fluoxetine (Prozac), sertraline (Zoloft®),venlafaxine (Effexor®), citalopram (Celexa®), parocetine (Paxil),mixtures thereof, and the like (such as trazodone (Desyrel)), and/orserotonin-norepinephrine reuptake inhibitors (SNRI), such asDesvenlafaxine (Pristiq®), Duloxetine (Cymbalta®), Milnacipran (Ixel®,Savella®), Venlafaxine (Effexor®), mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is anorepinephrine-dopamine reuptake inhibitor (NDRI), such as Amineptine(Survector®), an aminoketone antidepressant such as Bupropion(Wellbutrin®, Zyban®), Dexmethylphenidate (Focalin), Methylphenidate(Ritalin®, Concerta®), Nomifensine (Merital®), a phenylpiperazineantidepressant such as nefazodone (Serzone®), a piperazino-azepineantidepressant such as mirtazapine (Remeron®), mixtures thereof, and thelike.

In yet other embodiments, the additional drug(s) may be an NMDA receptorantagonist. Phencyclidine, ketamine, and dextromethorphan, are used asrecreational drugs. At subanesthetic doses, however, these drugs havemild stimulant effects, and these agents have shown promise for thetreatment of conditions that involve excitotoxicity, including traumaticbrain injury, stroke, and neurodegenerative diseases such asAlzheimer's, Parkinson's, and Huntington's.

Additionally, the additional drug(s) may be an agent that treatsneuropathic/neurogenic pain (pain that arises from nerve dysfunction andnot as a result of injury, e.g., trigeminal neuralgia), such ascarbamazepine, gabapentin, topiramate, zonisamide, phenytoin,desipramine, amitriptyline, imipramine, doxepin, protriptyline,pentoxifylline, and hydroxyzine.

In other embodiments, the additional drug(s) treats insomnia, such aszolpidem (Ambien®).

In other embodiments, the additional drug(s) treats fatigue. Such drugsinclude central nervous system stimulants such as pemoline (Cylert®) andModafinil (Provigil®).

In yet other embodiments, the additional drug(s) treats vertigo, nauseaand/or dizziness, such as meclizine (Antivert®), dimenhydrinate(36qualene36), prochlorperazine (36qualene36®), scopolamine (Transderm®)and diphenhydramine (Benadryl®).

In yet other embodiments, the drug is a serotonin-norepinephrinereuptake inhibitor (SNRI), such as Desvenlafaxine (Pristiq®), Duloxetine(Cymbalta®), Milnacipran (Ixel®, Savella®), Venlafaxine (Effexor®),mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is a tricyclicantidepressant (TCA), such as Amitriptyline (Elavil®), Butriptyline(Evadene®, Evadyn®e), Clomipramine (Anafranil®), Desipramine(Norpramin®, Pertofrane), Dosulepin (Prothiade), Doxepin (Adapin,Sinequan), Imipramine (Tofranil®), Lofepramine (Feprapax®, Gamanil®,Lomont®), Nortriptyline (Aventyl®, Nortrilen®, Pamelor®), Protriptyline(Vivacti®l), Trimipramine (Surmontil®), mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is a tetracyclicantidepressant, such as Amoxapine (Asendin®), Maprotiline (Ludiomil®),Mianserin (Tolvon®), mixtures thereof, and the like.

In yet other embodiments, the additional drug(s) is an atypicalantipsychotic, such as Ziprasidone (Geodon®, Zeldox®), Nefazodone(Serzone®), and the like.

In yet other embodiments, the additional drug(s) is an anti-convulsantor anti-epileptic drug such as arylsulfonimide analogues such asAcetazolimide (Diamox)®, tricyclic iminostilbene derivatives such ascarbamazepine (Tegreto®), benzodiazepines such as clonazepam(Klonopin®), clorazepate dipotassium (Tranxene®), lorazepam (Ativan®)and diazepam (Valium®), carboxylic acid derivatives such as valproicacid (Depakene®) and divalproex sodium (Depakote®), succinimidederivatives such as ethosuximide (Zarontin®), carbamate esters of2-phenyl-1,3-propanediol such as felbamate (felbatol®), hydantoins suchas phenytoin (Dilantin®), phenytoin sodium (Dilantin®) and fosphenytoinsodium (Cerebyx®), structural analogues of GABA such as gabapentin(Neurontin®) and pregabalin (Lyrica®), phenyltriazines such aslamotrigine (Lamictal®), pyrrolidine derivatives such as levitiracetam(Keppra®), tricyclic iminostilbene derivatives such as 37qualene37pine(Trileptal), barbiturates such as Phenobarbital, desoxybarbiturates suchas primidone (Mysoline®), nipecotic acid derivatives such as tiagabinehydrochloride (Gabitril®), sulfamated monosaccharides such as topiramate(Topamax®), oxazolidinedione derivatives such as trimethadione(Tridione®), and methanesulfonamides such as zonisamide (Zonigran®).Additional drugs such as Retigabine® (Valeant Pharmaceuticals),Lacosamide® (Schwarz Biosciences), and Perampanel® (Eisai) are indevelopment as anti-epileptics and neuromodulators for other associatedneurological, pain, and psychiatric conditions, and thus are furtherexamples of potentially useful drugs in the present invention.

In yet other embodiments, the additional drug(s) is ananalgesic/anti-inflammatory agent such as acetaminophen; prednisone,solumedrol, and other steroids; naproxen, aspirin, voltaren, ketoprofen,ibuprofen, nabumetone, and other NSAID's. The NSAID may be COX-1, COX-2or mixed COX-1/COX-2 inhibitors. Examples of COX-2 inhibitors includeoxicam, meloxicam, and the more selective celecoxib, rofecoxib,valdecoxib, parecoxib and etoricoxib. Further examples ofcorticosteroids include methylprednisolone, prednisolone, dexamethasone,and adreno-corticotrophic hormone (ACTH), corticotropin.

Additionally, the additional drug(s) may be an agent that treatsneuropathic/neurogenic pain (pain that arises from nerve dysfunction andnot as a result of injury, e.g., trigeminal neuralgia), such ascarbamazepine, gabapentin, topiramate, zonisamide, phenytoin,desipramine, amitriptyline, imipramine, doxepin, protriptyline,pentoxifylline, and hydroxyzine, mixtures thereof, and the like.

In other embodiments, the additional drug(s) is 4-aminopyridine (4-AP;also known as Fampridine®) or a pharmaceutically acceptable andtherapeutically active derivative thereof. This drug has been shown tohave the ability to improve the communication between damaged nerves,which may result in increased neurological function in the treatment ofconditions such as multiple sclerosis (MS). An example of another suchdrug is 3,4 diaminopyridine. In certain preferred embodiments, the 4-APis included in the formulation in an amount from about 1 mg to about 40mg, preferably about 2 to about 10 mg, and in certain embodiments mostpreferably about 5 mg.

In other embodiments, the additional drug(s) is useful for the treatmentof Dementia/Alzheimer's disease, such as Aricept®/donepezil,Exelon®/rivastigmine, Reminyl®/Razadyne®/galantamine, andNamenda®/memantine, their naturally occurring counterparts, and mixturesthereof.

In other embodiments, the additional drug(s) is a serotonin agonistuseful for the treatment of migraine, such as for example and withoutlimitation, sumatriptan, naratriptan, eletriptan, rizatriptan,zolmitriptan, almotriptan, frovatriptan, pharmaceutically acceptablesalts thereof, mixtures thereof, and derivatives thereof. Preferably theserotonin agonist is sumatriptan(3-(2-(dimethylamino)ethyl)-N-methyl-1H-indole-5-methanesulfonamide),one of its salts or derivatives. For migraine use, the additionaldrug(s) may further comprise an ergot alkaloid, such as for example andwithout limitation bromocriptine, ergocristine, ergocristinine,ergotamine, ergotaminine, ergocryptine, ergocryptinine, ergocornine,ergocorninine, ergosine, ergosinine, ergonovine, ergometrinine,dihydroergotamine, lisuride, d-lysergic acid, d-isolysergic acid,lysergol, lergotrile, metergoline, methysergide, methylergonovinepharmaceutically acceptable salts thereof, mixtures thereof, andderivatives thereof. Preferably the ergot alkaloid is ergotamine,dihydroergotamine, methysergide, salts, derivatives, active metabolitesor prodrugs thereof e.g., dihydroergotamine mesylate. As used herein,the identification of an agent(s) to be delivered includes not only theergot alkaloid per se but also its topically administrable prodrugs,active metabolites and prodrugs of the active metabolites.

In certain embodiments of the present invention, the serotonin agonistis in an amount of from about 0.5 mg to about 200 mg, preferably theserotonin agonist is in an amount of from about 0.5 mg to about 100 mg,and most preferably from about 10 mg to about 100 mg. In certainpreferred embodiments, the formulations of the present invention containsumatriptan base or a pharmaceutically acceptable salt thereof (e.g.,sumatriptan succinate). When the serotonin agonist is sumatriptan or apharmaceutically acceptable salt thereof, the amount of sumatriptan isin an amount of from about 0.5 mg to about 200 mg, preferably in anamount of from about 5 mg to about 200 mg, from about 5 mg to about 100mg, from about 5 mg to about 50 mg, or from about 5 mg to about 25 mg,and most preferably is in an amount of 12.5 mg, 25 mg, 50 mg or 100 mg.Comparative oral doses of certain triptans are as follows: sumatriptan,50 mg; rizatriptan, 10 mg; naratriptan, 2.5 mg; zolmitriptan, 2.5 mg;and eletriptan, 40 to 80 mg. Therefore, one skilled in the art canreadily determine therapeutically equivalent doses of serotonin agoniststhat may be useful in the present invention.

In other embodiments, the additional drug(s) is a skeletal musclerelaxant. Useful skeletal muscle relaxants include centrally actingskeletal muscle relaxants, and are not limited to for example andwithout limitation, afloqulone, baclofen, botulin toxins, carisoprodol,chlormezanone, chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine,clonazepam, diazepam, eperisone, idrocilamide, inaperisone, mephenesin,mephenoxalone, methocarbamol, metaxalone, mivacurium chloride,orphenadrine, phenprobamate, pridinol mesylate, quinine, tetrazepam,thiocolchicoside, tizanidine, tolperisone, pharmaceutically acceptablesalts thereof, active metabolites thereof, prodrugs thereof and mixturesthereof. Preferably the skeletal muscle relaxant is tizanidine base,tizanidine hydrochloride or any pharmaceutically acceptable saltsthereof, prodrugs thereof or mixtures thereof. In certain preferredembodiments where the skeletal muscle relaxant is tizanidine, the amountof tizanidine included in the formulation is from about 1 mg to about 10mg, preferably about 5 mg. One skilled in the art can readily determinetherapeutically equivalent doses of other skeletal muscle relaxants suchas those mentioned herein that may be useful in the present invention.

In certain embodiments, the topical formulation is used to treatinsomnia, and a therapeutically effective amount of a cannabinoid (e.g.,CBD) and a therapeutically effective amount of melatonin. Thetherapeutically effective amount of melatonin may be, for example, fromabout 0.05 mg to about 30 mg, and in certain preferred embodiments about5 mg.

In certain embodiments, the topical formulation is used to treatParkinson's disease, tremors and/or dystonia. In such embodiments, thetopical formulation comprises a therapeutically effective amount of acannabinoid (e.g., CBD) and a therapeutically effective amount ofapomorphine. The therapeutically effective amount of apomorphine may be,for example, from about 0.25 mg to about 4 mg, and in certain preferredembodiments about 2 mg.

In certain embodiments, the topical formulation is used to treatADD/ADHD and/or Tourette's syndrome. In such embodiments, the topicalformulation comprises a therapeutically effective amount of acannabinoid (e.g., CBD) and a therapeutically effective amount ofphentermine. The therapeutically effective amount of phentermine may be,for example, from about 5 mg to about 40 mg, and in certain preferredembodiments about 10 mg.

In certain embodiments, the topical formulation is used to treat anxietyand panic attacks, or mood disorders. In such embodiments, the topicalformulation may comprise a therapeutically effective amount of acannabinoid (e.g., CBD) and a therapeutically effective amount of anantidepressant (such as milnacipran or another serotonin-norepinephrinreuptake inhibitor (SNRI). The therapeutically effective amount ofmilnacipran may be, for example, from about 12.5 mg to about 100 mg, andin certain preferred embodiments about 25 mg.

In certain embodiments, the topical formulation is used to treatdiabetic peripheral neuropathy (DPN) and other peripheral neuropathicconditions. In such embodiments, the topical formulation may comprise atherapeutically effective amount of a cannabinoid (e.g., CBD) and atherapeutically effective amount of 4-aminopyridine or a therapeuticallyactive derivative thereof. The therapeutically effective amount of4-aminopyridine may be, for example, from about 5 mg to about 40 mg, andin certain preferred embodiments about 10 mg.

In certain embodiments, the topical formulation is used to treatspasticity and/or spasms. In such embodiments, the topical formulationmay comprise a therapeutically effective amount of a cannabinoid (e.g.,CBD) and a therapeutically effective amount a dopamine agonist (e.g.,apomorphine). The therapeutically effective amount of dopamine agonistmay be, for example, from about 0.25 mg to about 4 mg, and in certainpreferred embodiments about 2 mg. One skilled in the art can readilydetermine therapeutically equivalent doses of other dopamine agonistssuch as those mentioned herein that may be useful in the presentinvention.

In certain embodiments, the topical formulation is used to greatmigraine and/or tension headache. In such embodiments, the topicalformulation may comprise a therapeutically effective amount of acannabinoid (e.g., CBD) and a therapeutically effective amount of adopamine agonist such as sumatriptan and (optionally) a skeletal musclerelaxant (e.g., tizanidine). The therapeutically effective amount ofskeletal muscle relaxant may be, for example, from about 0.25 mg toabout 50 mg, and in certain preferred embodiments about 5 mg. Oneskilled in the art can readily determine therapeutically equivalentdoses of other skeletal muscle relaxants such as those mentioned hereinthat may be useful in the present invention.

Formulations

All currently approved therapies for the conditions described abovereach the central nervous system through the systemic circulation.Cerebral blood flow to brainstem structures is through the posteriorcirculation, via the vertebral and basilar arteries and their branches.In view of the undesirable side-effects associated with this form ofdrug delivery to the brain, it makes sense that targeted regionaldelivery to the brainstem is sought. Topical delivery of currently useddrugs compounded in an appropriate “dermal penetration enhancer” andapplied in cream/gel form or as a sustained-release patch at theposterior cervical region (back of the neck) at the hairline is such amethod. Lipoderm® is an example of an effective commercially availablecompounding medium. However, one skilled in the art will recognize thattopical carriers meeting the specific chemical requirements of anindividual drug can be formulated for maximum efficiency in topicaldelivery.

The formulations of the present invention are prepared such that thedrug(s) may be delivered acutely as single dose applications ascream/gel/ointment or as a sustained release topical patch, depending onthe condition treated and associated symptom complex in the individualpatient. The critical point, again, is in the location of theapplication: at the back of neck at the hair-line for access toposterior cervical afferents with free nerve endings under the surfaceof the skin. Through feedback connections with vagal and trigeminalafferent systems, this results in ultimate effect on brainstemstructures.

By virtue of the method of treatment described herein, the diseasestate/condition to be treated may be treated much faster and moreeffectively than such prior art modes of administration.

In certain embodiments of the present invention, the method of treatinga human patient comprises applying a topical formulation which comprisesa drug suitable for topical administration, which is useful for thetreatment of a disease state or condition treatable via the topicalbrainstem afferent stimulation (de-afferentation) drug therapy describedherein.

The methods of the present invention may also, if desired, involvepre-treatment of the skin with an enhancer to increase the permeabilityof the skin to the applied drug. The methods of the present inventionmay include pre-treatment or “prepping” of the skin area with asubstance that opens up the skin pores. Additionally, the methods of thepresent invention may include, if desired, pre-treatment or “prepping”of the skin with an alcohol swab or the like to rid the area of dirt,make-up, oil, and the like, prior to application of the drug.

In certain embodiments, the topical formulation of the present inventioncomprises a drug in an amount which is therapeutically effective whenadministered topically at the at the back of neck at the hair-line foraccess to posterior cervical afferents with free nerve endings under thesurface of the skin, but which provides a plasma concentration which issub-therapeutic if orally administered.

In certain embodiments, by applying the formulation of the presentinvention comprising a dose of drug at the back of neck at the hair-linefor access to posterior cervical afferents with free nerve endings underthe surface of the skin, it may be possible for the use of lower dosesof drug or faster relief of the headache than if applied to the trunk orlimbs of a human patient, and the lower plasma levels of drug whichresult from lower doses may thereby reduce unwanted side effects of thedrug.

The topical formulations of the present invention (e.g., ointment, gel,cream, or the like), must be suitable for topical administration of adrug, i.e., must contain pharmaceutically acceptable excipientscompatible with application to the skin tissue, and may optionallycontain a sufficient amount of an enhancer composition as describedhereinafter.

In certain embodiments, in addition to the drug (e.g., cannabinoiddrug(s)), the topical formulations and/or transdermal therapeuticsystems of the present invention may include at least one adjuvant suchas a penetration enhancer, anti-oxidant, stabilizer, carrier, orvehicle. Additionally or alternatively, the present invention mayinclude the application of electric current (iontophoresis) forenhancing permeation of the cannabinoid drug(s).

Suitable penetration enhancers useful in the formulations of the presentinvention include but are not limited to isostearic acid, octanoic acid,oleic acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropylmyristate, butyl stearate, methyl laurate, diisopropyl adipate, glycerylmonolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether,polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol,diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethylethers, polyethylene oxide dimethyl ethers, dimethyl sulfoxide,glycerol, ethyl acetate, acetoacetic ester, N-alkylpyrrolidone, andterpenes.

In certain embodiments, the topical formulations comprising a drug in anointment, gel, cream or the like, will typically contain on the order ofabout 0.001 to about 80% by weight, preferably 0.01 wt. % to 50 wt. %drug (i.e., cannabinoid drug(s) plus optional additional drugs asdescribed herein), and about 0 wt. % to about 50.0 wt. %, preferablyfrom about 1 wt. % to about 30 wt. % of a permeation enhancercomposition, with the remainder of the composition comprising a carrieror vehicle. In certain preferred embodiments, the drug is included in acream or gel or ointment in a concentration of, e.g., 1 mg drug/ml ofcarrier (e.g., Lipoderm). However, it is to be understood that oneskilled in the art can increase the amount of carrier or change thecarrier and maintain or improve efficacy of the topical formulation forTRNA therapy. In certain preferred embodiments, the drug is applied as aunit dose at the back of the neck or at the BONATH in immediate releaseform (e.g., cream, ointment or gel) for acute treatment with acannabinoid drug as would be beneficial to a human patient. In suchinstances, it is preferred that the concentration of cannabinoid drug(s)included in the unit dose is from about 1 mg to about 100 mg, based oncannabidiol, or an therapeutically equivalent amount of anothercannabinoid drug(s) as described herein. In certain preferredembodiments, a unit dose of cannabinoid (e.g., CBD) is from about 5 mgto about 50 mg or from about 7.5 mg to about 30 mg. This may beadministered in a topical cream, ointment, gel or the like. For example,the topical formulation may be administered as a unit dose in an amountfrom about 0.5 g to about 1 g at a cannabinoid (e.g., CBD) concentrationfrom about 0.1% to about 5% (or more).

In certain embodiments, the topical formulations comprising acannabinoid drug(s) with or without additional drugs (collectivelyreferred to herein as “drug(s)”) in an ointment, gel, cream or the like,will typically contain on the order of about 0.001 to about 80% byweight, preferably 0.01 wt. % to 50 wt. % drug(s) or from about 0.5% toabout 5% drug(s); and about 0 wt. % to about 50.0 wt. %, preferably fromabout 1 wt. % to about 30 wt. % of a permeation enhancer composition,with the remainder of the composition comprising a carrier or vehicle.In certain preferred embodiments, the drug comprises CBD and is includedin a cream or gel or ointment in a concentration of, e.g., 1 mg drug/mlof carrier (e.g., Lipoderm). However, it is to be understood that oneskilled in the art can increase the amount of carrier or change thecarrier and maintain or improve efficacy of the topical formulation forTRNA therapy.

Suitable (optional) permeation enhancers may also be included in theformulations. Such enhancers include, but are not limited to,dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA),decylmethylsulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML),propylene glycol (PG), PGML, glycerol monolaurate (GML), lecithin, the1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Whitby Research Incorporated, Richmond, Va.), alcohols, andthe like. The permeation enhancer may also be a vegetable oil asdescribed in U.S. Pat. No. 5,229,130 to Sharma. Such oils include, forexample, safflower oil, cotton seed oil and corn oil.

Additional optional enhancers for use in conjunction with the presentinvention are lipophilic compounds having the formula [RCOO]n R′,wherein n is 1 or 2 and R is C1-C16 alkyl optionally substituted with 1or 2 hydroxyl groups, and R′ is hydrogen or C1-C16 alkyl optionallysubstituted with 1 or 2 hydroxyl groups. Within this group, a firstsubset of compounds are represented by the formula [CH3 (CH 2)m COO]n R′in which m is an integer in the range of 8 to 16, n is 1 or 2, and R′ isa lower alkyl (C1-C3) residue that is either unsubstituted orsubstituted with one or two hydroxyl groups. Preferred enhancers withinthis group include an ester which is a lower alkyl (C1-C3) laurate(i.e., m is 10 and n is 1) such as “PGML”. It will be appreciated bythose skilled in the art that the commercially available material soldas “PGML” is typically although not necessarily a mixture of propyleneglycol monolaurate itself, propylene glycol dilaurate, and eitherpropylene glycol, methyl laurate, or both. Thus, the terms “PGML” or“propylene glycol monolaurate” as used herein are intended to encompassboth the pure compound as well as the mixture that is typically obtainedcommercially. Also within this group is a second subset of compounds,namely, esters of fatty alcohols represented by the formula CH3(CH2)m-O—CO—CHR1 R2, in which R1 and R2 are independently hydrogen,hydroxyl, or lower alkyl (C1-C3), and m is as above. Particularlypreferred enhancers within this group are lauryl lactate and myristyllactate. In addition, a third subset of compounds within this group areanalogous fatty acids, i.e., acids having the structural formula CH3(CH2)m COOH where m is as above. A particularly preferred acid is lauricacid.

Other optional enhancer compositions are wherein a lipophilic compoundas just described, particularly PGML is combined with a hydrophiliccompound, such as a C2-C6 alkanediol. One preferred hydrophilic enhancerwithin this group is 1,3-butanediol. Such enhancer compositions aredescribed in detail in PCT Publication No. WO 95/05137, published Feb.23, 1995, herein incorporated by reference. Another hydrophilic enhancerthat may be included in these compositions is an ether selected from thegroup consisting of diethylene glycol monoethyl ether (Transcutol) anddiethylene glycol monomethyl ether. Such enhancer compositions aredescribed in detail in U.S. Pat. Nos. 5,053,227 and 5,059,426 to Chianget al., the disclosures of which are herein incorporated by reference.

Other optional enhancer compositions may include mixture or combinationsof any of the aforementioned enhancers, and the like.

One preferred topical formulation comprises the cannabinoid drug(s) inoil, together with a suitable amount of a penetration enhancer, dimethylsulfoxide and a base. For example, such a formulation may include theCBD oil, and about 3 ml dimethyl sulfoxide in 30 g of base. The CBD canbe incorporated at a concentration of, e.g., from about 0.5% to about 5%of the topical formulation in a preferred embodiment, and mostpreferably from about 1.5% to about 3% in a certain embodiment. The doseof such a formulation would be, e.g., from about 0.5 g to about 1 gapplied topically on the back of the neck of the human patient.

U.S. Patent Publication No. 20080112895, hereby incorporated byreference, describes a room temperature stable aqueous cannabinoidformulation comprising an effective amount of a cannabinoid in asemi-aqueous solution buffered to a pH of about 5-1, the solutioncomprising water and an effective amount of an organic cosolvent tomaintain the physical stability of the formulation, which may beincorporated into a pharmaceutically acceptable carrier.

In certain embodiments the topical formulation may include at least onewater-insoluble, pharmacologically approved, alkyl cellulose orhydroxyalkyl cellulose, and the like. Alkyl cellulose or hydroxyalkylcellulose polymers for use in this invention include ethyl cellulose,propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropylcellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose,alone or in combination. In addition, a plasticizer or a cross linkingagent may be used to modify the polymer's characteristics. For example,esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asacid oleic and myristyl may be used in combination with the cellulosederivative.

In certain embodiments, the topical formulation may further includehydrocarbons such as liquid paraffin, qualene, solid paraffin,microcrystalline wax, etc.; higher aliphatic alcohols such as cetylalcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.;esters of higher fatty acids with higher alcohols such as beeswax, etc.;esters of higher fatty acids with lower alcohols such as isopropylmyristate, isopropyl palmitate, etc.; vegetable oils, modified vegetableoils, hydrous lanolin and its derivative, squalene, 47qualene; higherfatty acids such as palmitic acid, stearic acid, etc. and the like.

In certain embodiments, the topical formulation may further includeemulsifiers and dispersing agents which include, for example, anionic,cationic and nonionic surfactants. Nonionic surfactants are preferredbecause of their low levels of irritation to skin. Typical of nonionicsurfactants are fatty acid monoglycerides such as glyceryl monostearate,etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.;sucrose fatty acid esters; polyoxyethylene fatty acid esters such aspolyoxyethylene stearate, etc.; and polyoxyethylene higher alcoholethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,etc.

In certain preferred embodiments, the topical TRNA formulation isaqueous-based.

In certain embodiments of the present invention, the topical formulationmay include a gelling agent such as methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and thelike. Examples of pharmaceutical compositions which rely upon an aqueousgel composition as a vehicle for the application of a drug are U.S. Pat.Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780, thedisclosures of which are herein incorporated by reference.

The topical formulation may further include one or more preservatives,stabilizers, or anti-oxidants.

Examples of preservatives that may be used in a formulation according tothe present invention include, but are not limited to, bacteriostaticcompounds and other preservatives suitable for topical administrationincluding various alcohols, sorbic acid and salts and derivativesthereof, ethylenediamine, monothioglycerol, and thimerosal.

Examples of stabilizers that may be present in a formulation accordingto the present invention include pH buffers suitable for topicaladministration, complexing agents, chelating agents and the like.

Examples of anti-oxidants that may be used in a formulation according tothe present invention include ascorbic acid and its derivatives, e.g.,ascorbyl palmitate, as well as butylated hydroxyanisole, butylatedhydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.

Other adjuvants that may be included in the drug formulation includecarriers, tackifiers, pigments, dyes, and other additives that do notadversely affect the mechanical or adhesive properties of theformulation.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal drug administration, and include any suchmaterials known in the art, e.g., any liquid, gel, emulsion, solvent,liquid diluent, solubilizer, or the like, which is nontoxic and whichdoes not interact with other components of the composition in adeleterious manner. The term “carrier” or “vehicle” as used herein mayalso refer to stabilizers, crystallization inhibitors, dispersing agentsor other types of additives useful for facilitating transdermal drugdelivery. It will be appreciated that compounds classified as “vehicles”or “carriers” may sometimes act as permeation enhancers, and vice versa,and, accordingly, these two classes of chemical compounds orcompositions may sometimes overlap.

Carrier materials suitable for use in the instant compositions includethose well-known for use in the cosmetic and medical arts as bases forointments, lotions, salves, aerosols, suppositories and the like.Suitable carriers include, for example, water, liquid alcohols, liquidglycols, liquid polyalkylene glycols, liquid esters, liquid amides,liquid protein hydrolysates, liquid alkylated protein hydrolysates,liquid lanolin and lanolin derivatives, and like materials commonlyemployed in cosmetic and medicinal compositions. Other suitable carriersherein include for example alcohols, including both monohydric andpolyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.In certain preferred embodiments, the carrier is an aqueous basedcannabidiol cream is produced using Lipoderm® as the carrier.Lipoderm®/LIP is a whitish cream with no smell, commercially marketedcompounding agent (from PCCA, Pharmaceutical Compounding Centers ofAmerica) having the following ingredients: Ethoxydiglycol, Water (Aqua),Glycerin, C₁₂₋₁₅Alkyl Benzoate, Glyceryl Stearate, Dimethicone, CetearylAlcohol, Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, MagnesiumAluminum Silicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), TocopherylAcetate (Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond)Kernel Oil, Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare(Wheat) Germ Oil, Retinyl Palmitate (Vitamin A Palmitate), AscorbylPalmitate (Vitamin C Palmitate), Pro-Lipo Multi-emulsion LiposomicSystem, Tetrasodium EDTA, Phenoxyethanol, and SodiumHydroxymethylglycinate.

In certain embodiments of the invention, part or all of the dose ofcannabinoid drug(s) may be encapsulated within liposomes. For example,U.S. Patent Publication No. 2015/0302148, hereby incorporated byreference, describes fast-acting liposomal and micelle formulations ofcannabinoids which are prepared by (a) dissolving one or morecannabinoids or cannabinoid analogues in ethanol to obtain an ethanolcannabinoid solution; (b) adding a phospholipid to the ethanolcannabinoid solution to obtain an ethanol-phospholipid cannabinoidsolution; (c) injecting the ethanol-phospholipid cannabinoid solutioninto distilled water to obtain a liposomal cannabinoid suspension; and(d) removing the ethanol from the liposomal cannabinoid suspension,thereby producing a stable liposomal suspension of one or morecannabinoids or cannabinoid analogue. In certain embodiments, the methodfurther comprises the step of adding sodium alginate to the liposomalsuspension of one or more cannabinoids or cannabinoid analogues toobtain an alginate liposomal cannabinoid suspension that has a finalalginate concentration of 2% w/v, followed by the addition of calciumchloride to the alginate liposomal cannabinoid suspension to obtain acalcium alginate-encapsulated liposomal cannabinoid suspension. Thissuspension is then cold-pressed and air-dried to remove the water so asto obtain a dry cannabinoid powder. The dry cannabinoid powder can bere-suspended in citrate buffer to obtain an aqueous cannabinoidsolution. The amount of cannabinoid or cannabinoid analogue in theaqueous cannabinoid solution is greater than 40%.

In certain preferred embodiments of the present invention where it isdesired that the drug is administered chronically, the formulations ofthe present invention may be formulated as a transdermal delivery system(also referred to herein as a transdermal therapeutic system) such as atransdermal patch, a transdermal plaster, a transdermal disc,iontophoretic transdermal device, or the like. Such formulations arerecognized by those skilled in the art as providing a release of drugand absorption into the skin of the patient in a sustained manner overan extended period of time (e.g., 1-7 days). In such embodiments of thepresent invention, the transdermal delivery system comprises, e.g., acannabinoid drug(s) contained in a reservoir or a matrix, and anadhesive which allows the transdermal patch to adhere to the skin,allowing the passage of the active agent from the transdermal patchthrough the skin of the patient. In preferred embodiments, thetransdermal patch is applied topically at the back of the neck so as toachieve topical regional neuro-affective therapy (“TRNA THERAPY”) asdescribed herein. In embodiments in which the drug is contained in atransdermal patch, it is contemplated that the drug will be absorbedmore slowly and the transdermal patch will provide a sustained releaseand prolonged therapeutic effect, as compared, e.g., to a cream orointment intended to provide an immediate release of the drug and rapidonset of the TRNA therapy. In such embodiments, the dose of cannabinoiddrug(s) may be that which is sufficient to provide a therapeuticallyeffective dose to the back of the neck (e.g., non-systemic dose) overthe course of e.g., from about 1, 2, 3, 4, 5, 6 or 7 days. In certainembodiments, the dose of cannabinoid drug(s) contained in thetransdermal delivery system is from about 0.5 mg to about 1000 mg. Incertain preferred embodiments, the dose of the cannabinoid drug is fromabout 1 mg to about 100 mg. In certain preferred embodiments in whichthe cannabinoid drug is cannabidiol, the dosage is from about 8 mg toabout 80 mg, and in certain preferred embodiments, about 40 mg. As thereare only a finite number of receptors on the skin, once these receptorsare bound, the rest of the active drug is contained in the (e.g.,topical) preparation is superfluous. Therefore, there is no possibilityof “over-dosing,” only of extra drug of potentially irritating the skinsurface. Accordingly, in preferred embodiments, the methods andformulations of the present invention provide reduced side effects ascompared to a systemic administration of the same drug.

In certain embodiments, the transdermal delivery devices, as well asother transdermal delivery systems in accordance with the invention canbe made in the form of an article such as a tape, a patch, a sheet, adressing or any other form known to those skilled in the art. Generallythe device will be in the form of a patch of a size suitable to delivera unit dose of serotonin agonist through the skin. The drug may beintroduced into a transdermal therapeutic system in different forms(solid, in solution, in dispersion); it may also be microencapsulated.

In certain embodiments the present invention provides a transdermaltherapeutic system comprising a cannabinoid drug(s) in an amount thatwould provide sub-therapeutic plasma levels if administered orally, butis therapeutically effective when administered via transdermal deliveryat the back of the neck.

A transdermal delivery system for use in accordance with the presentinvention can also be constructed with an enhancer composition and otheringredients described hereinabove with respect to the topicalformulation. Preferably, the transdermal delivery system is formulatedfor the prolonged delivery of the cannabinoid drug(s). The targeted skinflux for delivery of the cannabinoid drug(s) can be achieved byadjusting vehicle composition and vehicle loading, as well as byadjusting the surface area through which the compositions areadministered to skin.

In certain preferred embodiments, the transdermal delivery system (e.g.,patch) is formulated to deliver from about 1 mg to about 800 mg of thecannabinoid drug(s) per each 24 hours through the skin of the patient,based on cannabidiol (CBD), or a therapeutically equivalent amount of asuitable alternative cannabinoid(s) as described herein. In embodimentsin which the transdermal delivery system is intended to be applied tothe skin at the back of the neck for multiple days, the transdermaldelivery system (e.g., patch) is formulated to provide a flux rate overthe useful life of the system such that a similar amount (e.g., meandose) is delivered on a daily basis until the system is removed andreplaced with a fresh system.

The transdermal delivery system used in the present invention may beprepared, for example, in accordance with U.S. Pat. Nos. 5,069,909;4,806,341; 5,026,556; 4,588,580; 5,016,652; 3,598,122; 4,144,317;4,201,211; 4,262,003; and 4,379,454; all of which are incorporatedherein by reference.

Additionally, the transdermal delivery system used in the presentinvention may be in accordance with U.S. Pat. No. 6,689,379, herebyincorporated by reference, which system is a matrix or reservoir systemwhich comprises at least one pharmaceutical active agent and apressure-sensitive adhesive comprising a polyacrylate polymer, whereinsaid polyacrylate polymer has a polyacrylate backbone containing monomerunits selected from the group consisting of acrylic acid, methacrylicacid and ester derivatives of acrylic or methacrylic acid, and saidmonomer units comprise at least 50% (w/w) relative to a mean polymermass of said polyacrylate polymer, a total amount of monomers selectedfrom the group consisting of non-esterified acrylic acid andnon-esterified methacrylic acid is 0.5 to 10.0% (w/w) relative to themean polymer mass of said polyacrylate polymer, and the carboxyl groupsof said non-esterified acrylic and methacrylic acid monomers are presentstoichiometrically at 5 to 100% in the form of alkali salts oralkaline-earth salts, said salts being reaction products of aneutralization reaction of an alcoholic solution of an alkalinehydroxide or an alkaline-earth hydroxide with said acrylate polymer(s),or of a neutralization reaction of an alkali alcoholate or analkaline-earth alcoholate with said acrylate polymer(s).

In certain embodiments, the dosage form can be a transdermal patchcomprising a laminated composite for administering the drug (e.g.,cannabinoid drug(s)) to an individual transdermally comprising: (a) apolymer backing layer that is substantially impermeable to thecannabinoid drug(s); and (b) a reservoir layer comprising a water-baseacrylate pressure-sensitive adhesive, 1 to 12% by weight serotoninagonist and 2 to 25% by weight of a permeation enhancer comprisingpropylene glycol monolaurate in combination with capric acid or oleicacid, wherein the skin contact area of the composite is 10 to 100 cm2.

The dosage form can be a transdermal patch comprising (a) a polarsolvent material selected from the group consisting of C3-C4 diols,C3-C6 triols, and mixtures thereof; and (b) a polar lipid materialselected from the group consisting of fatty alcohol esters, fatty acidesters, and mixtures thereof; wherein said polar solvent material andsaid polar lipid material are present in a weight ratio of solventmaterial:lipid material of from about 60:40 to about 99:1.

In certain embodiments, the dosage form also comprises a transdermalplaster comprising: (1) a film layer which comprises a polyester film of0.5 to 4.9 microns thickness, 8 to 85 g/mm strength, respectively in thetwo directions intersecting substantially at right angles, 30 to 150%elongation, in the two directions intersecting substantially at rightangles and an elongation ratio of A to B of 1.0 to 5.0, wherein A and Brepresent data in two directions intersecting at right angles, and A isgreater than B, and wherein said polyester film comprises 0.01 to 1.0%by weight, based on the total weight of said polyester film, of solidfine particles in which (a) the average particle size is 0.001 to 3.0microns, and (b) the average particle size is substantially not morethan 1.5 times the thickness of said polyester film; and (2) an adhesivelayer (a) which is composed of an adhesive containing said serotoninagonist and further wherein said adhesive layer (a) is laminated on saidfilm layer over the surface in a 2 to 60 microns thickness.

In certain embodiments, the dosage form can be a transdermal disccomprising: (a) a backing layer which is substantially impervious to thecannabinoid drug(s); and (b) a polymer matrix disc layer which isadhered to said backing layer and which has microdispersed therein saidserotonin agonist, said polymer being bioacceptable and permitting saidserotonin agonist to be transmitted for transdermal absorption, thecannabinoid drug(s) being stable in said polymer matrix.

In certain embodiments, the topical formulation or transdermaltherapeutic system may further comprise another active ingredient incombination with the first drug (e.g., as previously described herein).

The present invention is contemplated to encompass all transdermalformulations, e.g., the technologies described above, with the inclusionof the cannabinoid drug(s), such that the administration of a druguseful for treatment of disease state or condition in humans via topicalbrainstem afferent stimulation (de-afferentation) therapy via topicaladministration. Therefore, modifications of the invention via, e.g., thechoice and/or amount of drug are considered to be obvious variations ofthis disclosure and within the scope of the appended claims.

The present invention also contemplates the administration of thecannabinoid drug (s) directly below the skin to affect direct brainstemafferent stimulation to the free nerve endings under the epidermis. Suchadministration may be effected as an injection (e.g., subcutaneousinjection) or implantation of the drug in immediate release or sustainedrelease form. It will be appreciated by those skilled in the art thatproviding the drug in sustained release form and administering it in asuitable form below the skin may provide benefits, including lessfrequent administration (e.g., in chronic therapy).

In certain embodiments of the invention, the cannabinoid drug(s) can beformulated for controlled or sustained delivery at the back of the neckvia incorporation into a biocompatible and implantable polymer which canbe in the form of microparticles or an implantable insert, or a liquidthat forms a gel or colloid or a semi-solid after injection (therebyencapsulating the drug and allowing it to be released in a prolonged andcontrolled manner at the desired site). For chronic conditions (e.g.,Parkinson's) or desired prolonged effect, it is contemplated that a drugdepot or reservoir may be created under the skin at the back of theneck, which then provides a sustained release of the drug in proximityto the desired nerve endings and which may be replenished or replaced atthe end of the dosing interval. It is contemplated that suchadministrations of the drug may provide a prolonged therapeutic effectfor at least about 3 days, preferably at least about 7 days, or longer.Such formulations may be administered in certain embodiments as, forexample, a subcutaneous depot.

Implants are placed subcutaneously by making an incision in the skin andforcing the implants between the skin and the muscle. At the end oftheir use, if not dissolved, these implants are surgically removed. U.S.Pat. No. 4,244,949, hereby incorporated by reference, describes animplant which has an outer matrix of an inert plastic such aspolytetrafluoroethylene resin. Examples of this type of implantabletherapeutic system are Progestasert IUD and Ocusert system. It iscontemplated that such systems can be appropriately modified by oneskilled in the art for use in conjunction with the present invention. Acommercially available product, Norplant®, which is an implant having acore containing levonorgestrel as the active substance, and where thecore it surrounded by a membrane of a silicone elastomer ofpoly(dimethylsiloxane) (PDMS). Another preparation of this kind isJadelle®, in which the core is a poly(dimethylsiloxane) based matrixwith levonorgestrel dispersed therein. The membrane is an elastomer madefrom PDMS and silica filler, which, besides giving necessary strengthproperties to the membrane, also retards the permeation of the activeagent through the membrane. U.S. Pat. No. 3,854,480, hereby incorporatedby reference, describes a drug delivery device, e.g. an implant, forreleasing a drug at a controlled rate for a prolonged period of time.The device has a core of a matrix in which the drug is dispersed. Thecore is surrounded by a membrane that is insoluble in body fluids. Thecore matrix as well as the membrane are permeable to the drug bydiffusion. The materials of the core and the membrane are chosen so thatthe drug diffuses through the membrane at a lesser rate than through thecore matrix. Thus, the membrane controls the release rate of the drug.As a suitable polymer for the core matrix is mentionedpoly(dimethylsiloxane) (PDMS), and as suitable polymers for the membraneare mentioned polyethylene and a copolymer of ethylene and vinyl acetate(EVA). It is contemplated that the above systems may be adapted by oneskilled in the art to deliver the cannabinoid drug(s) in accordance withthe present invention.

One device which may be adapted by one skilled in the art for use in thepresent invention is described in U.S. Pat. No. 5,968,542 (Tipton),hereby incorporated by reference, which describes a high viscosityliquid controlled delivery system as a medical or surgical device isprovided that includes: (i) a non-polymeric, non-water soluble liquidcarrier material (HVLCM) of viscosity of at least 5,000 Cp at 37° C.that does not crystallize neat under ambient or physiologicalconditions; and, optionally, (ii) a substance to be delivered.

The pharmaceutical compositions suitable for injectable use inaccordance with this invention include sterile aqueous solutions ordispersions and sterile powders or lyopholysates for the extemporaneouspreparation of sterile injectable solutions or dispersions. The dosageforms must be sterile and it must be stable under the conditions ofmanufacture and storage. The carrier for injectable formulations istypically water but can also include ethanol, a polyol (for example,glycerol, propylene glycol and liquid polyethylene glycol), mixturesthereof, and vegetable oil.

Injectable formulations used in the present invention can also beformulated as injectable prolonged release formulations in which theactive compound is combined with one or more natural or syntheticbiodegradable or biodispersible polymers such as carbohydrates,including starches, gums and etherified or esterified cellulosicderivatives, polyethers, polyesters, polyvinyl alcohols, gelatins, oralginates. Such dosage formulations can be prepared for example in theform of microsphere suspensions, gels, or shaped polymer matrix implantsthat are well-known in the art for their function as “depot-type” drugdelivery systems that provide prolonged release of the biologicallyactive components. Such compositions can be prepared usingart-recognized formulation techniques and designed for any of a widevariety of drug release profiles.

One example of a useful formulation which may be used in the methods ofthe present invention for providing a prolonged duration of action isdescribed in U.S. Pat. No. 7,332,503 (Wikstrom, et al.), herebyincorporated by reference. Therein, apomorphine derivatives and thephysiologically acceptable salts thereof as well as formulations thereofare described which provide a prolonged duration of action. Theapomorphine pro-drugs can be suspended (as a neat oil or as crystals, ordissolved in a suitable and pharmaceutically acceptable solvent (e.g.water, ethanol, DMSO, i-PrOH or benzylbenzoate)) in a pharmaceuticallyacceptable depot oil (e.g. viscoleo, sesame oil or olive oil) andinjected subcutaneously or intramuscularly with a syringe or a “peninjector”. Alternatively, these drugs may, in a suitable composition andwith a suitable vehicle (penetration enhancer), be applied to a patchfor transdermal administration. The composition could include also alocal anesthetic (e.g. lidocaine) to avoid injection pain, in particularat intramuscular injections. In one embodiment, the composition is inthe form of a patch or an ointment for transdermal administration. Thepatch or ointment preferably also comprises stabilizers, solubilizersand permeation activators to facilitate the passage of the activeprinciple through the skin. In another preferred embodiment, thecomposition is in the form of a depot preparation for subcutaneous orintramuscular administration comprising the cannabinoid drug(s)dissolved or suspended in an oil. In certain embodiments, in addition tothe apomorphine derivative, the formulation further contains a localanesthetic. The formulations described in the '503 patent can bemodified as understood by one skilled in the art to contain other activedrugs as described herein for use at the back of the neck, e.g., BONATH.

An injectable depot formulation is a dosage form, which is generallyintended to have a therapeutic activity for 2 to 4 weeks afteradministration (e.g. in sesame oil). In order to maintain effective drugplasma levels the dosage form should release the drug at a more or lessconstant rate during the desired dosing interval. The difference betweensuch prior art depots and depots used in the present invention is thatthe in accordance with the present invention, the drug is not needed tobe absorbed into the systemic circulation.

A suitable form of depot preparation is the subcutaneous orintramuscular administration of an oil solution and/or oil suspension ofa lipophilic drug. This gives a slow transport over the oil-biofluidinterface and a slow dissolution in the biophase. Thus, when the drug isdissolved in a polar solvent (e.g. oils), which is non-miscible with theaqueous biological fluids, the drug has to be transported over theoil/water interface. When the oil/water partition coefficient is high,the transport will be slow. For very lipophilic drugs, the release fromthe oil phase may last for up to several weeks. The use of depotpreparations such as those described herein may be used to deliver thedrugs described herein at the back of the neck, e.g., BONATH.

The maximum volume of an oil solution/suspension to be injectedintramuscularly or subcutaneously is 2-4 Ml. This is feasible for thepreparations of the cannabinoid drug formulations of the presentinvention. For example, the cannabinoid drug(s) may be dissolved ordispersed in 1 Ml of an oil (sesame oil, Viscoleo or another approvedoil) and the mixture gently heated (max 50° C.) shaken in a test tubeshaker and ultrasonicated for a short time (minutes) until the mixturebecomes a homogeneous solution or suspension. If necessary, thecannabinoid drug(s) may first be dissolved in 50-300 μl DMSO, water,t-BuOH, PEG, benzylbenzoate, or another suitable and approved solvent ormixtures thereof, before adding the oil to a total volume of 1 Ml.

Another example of a polymeric drug delivery system which may be adaptedfor use in the present invention by one skilled in the art is describedin U.S. Pat. No. 5,601,835 (Sabel, et al.), hereby incorporated byreference, which describes a polymeric drug delivery system for deliveryof any substance to the central nervous system. The delivery system ispreferably implanted in the central nervous system for delivery of thedrug directly to the central nervous system. These implantable devicescan be used, for example, to achieve continuous delivery of dopamine,which cannot pass the blood brain barrier, directly into the brain foran extended time period. The implantable devices display controlled,“zero-order” release kinetics, a life time of a minimum of several weeksor months even when the devices contain water soluble, low molecularweight compounds, biocompatibility, and relative non-invasiveness. Thepolymeric devices are said to be applicable in the treatment of avariety of central nervous system disorders including Parkinson'sdisease, Alzheimer's dementia, Huntington's disease, epilepsy, trauma,stroke, depression and other types of neurological and psychiatricillnesses, and one skilled in the art can adapt that drug deliverysystem for delivering the drugs contemplated herein at the back of theneck, e.g., BONATH.

Yet another example of a system that may be adapted for use in thepresent invention is described in U.S. Pat. No. 5,601,835 (Sabel, etal.), hereby incorporated by reference, wherein an active compound isencapsulated within a polymer to form a polymeric device, the deviceformed of a biocompatible polymer that is plastically deformableselected from the group consisting of ethylene vinyl acetate,polyurethanes, polystyrenes, polyamide, polyacrylamide, and combinationsthereof having a non-porous polymer coating thereon with one or moreopenings, with limited water sorptivity and slight permeability to thepassage of small, aqueous-soluble molecules, wherein said compound islinearly released (e.g., zero order release) from said polymeric deviceover a sustained period of time of at least 65 days at a predeterminedlevel and rate when implanted in a patient at a specific site within thecentral nervous system where the compound is released directly into thecentral nervous system and the device remains essentially intactthroughout the release period. The delivery device is a two-phase systemthat is manufactured using standard techniques such as blending, mixingor the equivalent thereof, following selection of the biologicallyactive material to be delivered and an appropriate polymer for formationof the matrix. The general method of solvent casting as disclosed bySiegel and Langer, “Controlled release of polypeptides and othermacromolecules”, Pharmaceutical Research 1, 2-10 (1984), is modified sothat drug is dispersed within the devices to create channels and poresto the surface for release of the drug at the desired rate. Whereappropriate, a coating impermeable to the drug is placed over a portionof the drug containing polymer matrix to further regulate the rate ofrelease. One skilled in the art can adapt that drug delivery system fordelivering the drugs contemplated herein at the back of the neck, e.g.,BONATH.

Yet another formulation which may used to deliver the drug as set forthin the present invention at the back of the neck, e.g., BONATH, isdescribed in U.S. Pat. No. 7,314,636 (Caseres et al.), herebyincorporated by reference, which describes injectable implantscomprising glycolic acid and bio-compatible/bio-absorbable polymericparticles containing a polymer of lactic acid. The particles are smallenough to be injected through a needle but large enough to avoidengulfment by macrophages. The injectables of this invention may be in apre-activated solid form or an activated form (e.g., injectablesuspension or emulsion).

It is further contemplated that the system described in U.S. Pat. No.6,586,006 (Roser, et al.), hereby incorporated by reference, can beadapted by one skilled in the art for use in the present invention fordelivery of drugs at the back of the neck, e.g., BONATH. Therein aredescribed delivery systems suitable for delivery of bioactive materialsto subcutaneous and intradermal, intramuscular, intravenous tissue, thedelivery system being sized and shaped for penetrating the epidermis.The delivery systems comprise a vitreous vehicle loaded with the guestsubstance and capable of releasing the guest substance in situ atvarious controlled rates. Subdermal implantable therapeutic systems havealso been formulated for slow release of certain pharmaceutical agentsfor extended periods of time such as months or years. A well-knownexample is Norplant® for delivery of steroid hormones.

In membrane permeation-type controlled drug delivery, the drug isencapsulated within a compartment that is enclosed by a rate-limitingpolymeric membrane. The drug reservoir may contain either drug particlesor a dispersion (or solution) of solid drug in a liquid or a matrix typedispersing medium. The polymeric membrane may be fabricated from ahomogeneous or a heterogeneous nonporous polymeric material or amicroporous or semipermeable membrane. The encapsulation of the drugreservoir inside the polymeric membrane may be accomplished by molding,encapsulation, microencapsulation, or other techniques. The implantsrelease drugs by dissolution of the drug in the inner core and slowdiffusion across the outer matrix. The drug release from this type ofimplantable therapeutic system should be relatively constant and islargely dependent on the dissolution rate of the drug in the polymericmembrane or the diffusion rate across or a microporous or semipermeablemembrane. The inner core may substantially dissolve over time; however,in devices currently in use, the outer matrix does not dissolve.

Other implantable therapeutic systems involve matrix diffusion-typecontrolled drug delivery. The drug reservoir is formed by thehomogeneous dispersion of drug particles throughout a lipophilic orhydrophilic polymer matrix. The dispersion of drug particles in thepolymer matrix may be accomplished by blending the drug with a viscousliquid polymer or a semisolid polymer at room temperature, followed bycross-linking of the polymer, or by mixing the drug particles with amelted polymer at an elevated temperature. It can also be fabricated bydissolving the drug particles and/or the polymer in an organic solventfollowed by mixing and evaporation of the solvent in a mold at anelevated temperature or under vacuum. The rate of drug release from thistype of delivery device is not constant. Examples of this type ofimplantable therapeutic system are the contraceptive vaginal ring andCompudose implant. PCT/GB 90/00497 describes slow release glassy systemsfor formation of implantable devices. The described implants arebioabsorbable and need not be surgically removed. One skilled in the artcan adapt these drug delivery systems for delivering the drugscontemplated herein at the back of the neck, e.g., BONATH.

In microreservoir dissolution-controlled drug delivery, the drugreservoir, which is a suspension of drug particles in an aqueoussolution of a water-miscible polymer, forms a homogeneous dispersion ofa multitude of discrete, unleachable, microscopic drug reservoirs in apolymer matrix. The microdispersion may be generated by using ahigh-energy-dispersing technique. Release of the drug from this type ofdrug delivery device follows either an interfacial partition or a matrixdiffusion-controlled process. An example of this type of drug deliverydevice is the Syncro-Mate-C Implant.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 6,576,263(Truong, et al.), hereby incorporated by reference, which describes apreformed object for delivering an active agent for a subject, thepreformed object including cross-linked protein, and methods of makingand using.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 6,287,588(Shih, et al.), hereby incorporated by reference, which describes acomposition and method for releasing a bio-active agent or a drug withina biological environment in a controlled manner. The composition is adual phase polymeric agent-delivery composition comprising a continuousbiocompatible gel phase, a discontinuous particulate phase comprisingdefined microparticles and an agent to be delivered. A microparticlecontaining a bio-active agent is releasably entrained within abiocompatible polymeric gel matrix. The bio-active agent release may becontained in the microparticle phase alone or in both the microparticlesand the gel matrix. The release of the agent is prolonged over a periodof time, and the delivery may be modulated and/or controlled. Inaddition, a second agent may be loaded in some of the microparticlesand/or the gel matrix.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 7,364,568(Angel, et al.), hereby incorporated by reference, which describes atransdermal transport device includes a reservoir for holding aformulation of an active principle, and a needle with a bore extendingalong the length of the needle from a first end of the needle to asecond end of the needle. The second end is substantially aligned to aplane parallel to a body surface of a biological body when the device isplaced on the body surface. The device also includes an actuator whichpumps the formulation through the bore of the needle between a targetarea of the body and the reservoir.

In yet other embodiments of the invention, the cannabinoid drug(s) isinfused into the patient at the back of the neck using technology knownto be useful for infusing other drugs, such as an insulin pump. One suchsystem, U.S. Pat. No. 7,354,420 (Steil, et al.), hereby incorporated byreference, describes a closed loop infusion system controls the ratethat fluid is infused into the body of a user. The closed loop infusionsystem includes a sensor system, a controller, and a delivery system.The sensor system includes a sensor for monitoring a condition of theuser. The sensor produces a sensor signal, which is representative ofthe condition of the user. The sensor signal is used to generate acontroller input. The controller uses the controller input to generatecommands to operate the delivery system. The delivery system infuses aliquid into the user at a rate dictated by the commands from thecontroller. Preferably, the sensor system monitors the glucoseconcentration in the body of the user, and the liquid infused by thedelivery system into the body of the user includes insulin.

The present invention is contemplated to encompass all implantable orinjectable formulations, e.g., the technologies described above, withthe inclusion of a drug(s) (e.g., cannabinoid drug(s)(s)), such that theadministration of a drug useful for treatment of disease state orcondition in humans via topical brainstem afferent stimulation(de-afferentation) therapy. Therefore, modifications of the inventionvia, e.g., the choice and/or amount of drug are considered to be obviousvariations of this disclosure and within the scope of the appendedclaims.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction on the generality of the invention specifiedabove.

EXAMPLE 1 Topical Formulation

An aqueous based cannabidiol cream is produced using Lipoderm® as thecarrier. Lipoderm®/LIP is a commercially marketed compounding agent(from PCCA, Pharmaceutical Compounding Centers of America) having thefollowing ingredients: Ethoxydiglycol, Water (Aqua), Glycerin,C₁₂₋₁₅Alkyl Benzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol,Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, Magnesium AluminumSilicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate(Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil,Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil,Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin CPalmitate), Pro-Lipo Multi-emulsion Liposomic System, Tetrasodium EDTA,Phenoxyethanol, and Sodium Hydroxymethylglycinate. The concentration is4 mg of CBD in 1 ml of Lipoderm. Lipoderm is a whitish cream with nosmell. The cannabinoid drug(s) are incorporated into the Lipoderm creamin the form of a CBD oil product as described herein.

EXAMPLE 2

A 60 g topical formulation of CBD is prepared by incorporating 2.2 g CBD(CBD-RSHO-Clear 43.5%), 20 g Pluronic 20%, 40 g Carbomer hydroalcoholicgel and 1 ml ethyl alcohol to obtain a CBD topical formulation having a1.6% concentration of CBD.

EXAMPLE 3 Oil-Based CBD

A 30 g topical formulation of CBD is prepared by incorporating CBD oil,Dimethyl sulfoxide 3 ml and enough base for total quantity of 30 grams.The CBD is incorporated in a concentration sufficient to yield an endproduct having a CBD concentration of 0.75%, 1%, 1.5%, 2% and 3%. Thetopical formulation is in the form of a cream. The oil-based CBDincludes CBD oil commercially available from CannaVest. A unit dose ofthe topical CBD cream is from about 0.5 to about 1 g, with respect toformulations having a CBD concentration from 1.5%-3%. After initialapplication, the topical CBD formulation can be applied to the back ofthe neck of the human patient once a day, twice a day, three times aday, or four times a day depending on the condition to be treated andits severity.

EXAMPLE 4 CBD Crystalline Powder

A 60 g topical formulation of CBD is prepared utilizing CBD crystallinepowder (95%+pure CBD). The CBD is incorporated into the topicalformulation of Example 2 having a CBD concentration between 0.75% toabout 10% CBD.

EXAMPLE 5

The following patients were treated with a topical cannabidiol (CBD)formulation administered on the back of the neck on human patients at a40 mg dose, as more specifically described below in Table 1:

TABLE 1  1. 33 y/o Haitian male with Seizures, impulsive behavior, 10minutes after topical CBD, neonatal brain damage, agitation,concentration and settled down playing games on chronic encephalopathyand attentional problems. On Trileptal, the phone and did not requireseizures. Seroquel, Klonopin, Diamax, and usual meds without which hewas Trazodone. Came in agitated and usually intolerable. Withhyperactive as he had not had continued use, mother states lessafternoon meds. agitated, more compliant, and sleeping better - allissues in the past.  2. 74 y/o female in Nursing Sitting in wheelchairwith eyes 10-15 minutes after nuchal topical Home with severe brain openwith blank stare, CBD, she “woke up” in front of damage from multipleunresponsive, not following RN daughter who called it “a strokes.commands or verbalizing, neglect miracle” smiling, responding of lefthemibody and not moving verbally, following simple it. On Namenda,Depakote, and commands using both sides of her Trazodone. body.  3. 75y/o female s/p head Slowed cognition, inattentive, flat More spontaneousand animated, injury from fall in bathroom affect with speech hesitancy.conversant, near back to 2 months prior. premorbid feisty personality. 4. 89 y/o female s/p hit by Confusion, decreased memory, More alert andless “fogginess” in car with head injury. feeling “foggy” in thoughts,thinking, speech spontaneous. insomnia with visual hallucinations;mumbling speech.  5. 66 y/o physician with s/p 4 cardiac surgeries under“felt more alert” more daytime hyper somnolence general anesthesiawithin short spontaneous and conversant and cognitive slowing. period oftime with “perfusion within 15 minutes. pump syndrome” and hypoxicencephalopathy.  6. 58 y/o male successful Cognitive impairmentdocumented Significant improved alertness, financial advisor and stockby formal neuropsychological more conversational, improved broker withclosed head testing and deemed disabled, memory also noted by wife whoinjury from auto accident. unable to return to work. On is a pharmacist“back to prior disability with persistent seizures, personality”. Willbegin process lethargy, cognitive slowing, on of reducing medications.Vyvanse, Gabapentin, Vimpat, Abilify, and tramadol.  7. 66 y/o maleParkinson's On apomorphine, selegiline, With one dose of 40 mg topicaldiseases x 4 years with on- Comtan, Neupro patch and CBD, no episodes offreezing for off phenomena and freezing tizanidine and experiencing10-12 over 24 hours; also more episodes. freezing episodes per day.spontaneous and with improved speech. Now on CBD 2x/day.  8. 68 y/o males/p 2 strokes First right brain stroke 18 months 40 mg topical CBDresulted in with left hand weakness and ago with recovery. Second strokesignificant improvement in left incoordination. 6 weeks ago withsignificant hand function within 15 minutes; impairment of the leftupper patient also more alert and extremity. conversant. Had beencomplaining of lethargy when he came in, which resolved.  9. 48 y/ofemale with neck Exam showed decreased range of After 40 mg topical CBD,pain and right upper motion of neck to right with improved neck range ofextremity numbness and moderate weakness of the right movement and rightupper weakness for a week after upper extremity. Pain level was 7extremity strength. Pain level heaving exercise. of 10. dropped to 2 of10. Prior insomnia improved. 10. 55 y/o female s/p Uncontrollablecentral 20 minutes after 40 mg topical intracranial aneurysmhypertension despite numerous CBD, NP dropped from 220/110 rupture.medications with headaches and to 180/100. Patient could tell centralpain syndrome. difference. 11. 14 y/o male inattention, Neonatal birthtrauma with ICU 5 minutes after 40 mg topical focusing problems, stayfor week, head injury at age 5. CBD, remarkable change noted agitation,oppositional Recent EEG showed cortical by father and teenage sister:calm, defiant behavior. irritability and potential for focused, notusual fidget seizures. behavior, and with eye contact. Patientrecognized himself “more calm.” 12. 58 y/o male bi-polar; On Depakote,trazodone, Vilibryd, 40 mg topical CBD resulted in cognitive problems,memory and Wellbutrin with abnormal improved clarity of thoughts, lapse,poor concentration, EEG suggesting cortical irritability better focus,and patient was and impulsivity. and seizures. brighter and morespontaneous. 13. 92 y/o female with Patient takes Ativan/LorazepamNuchal topical CBD 40 mg anxiety disorder and panic when she has panicattacks. She aborted panic attack and reduced attacks. was in midst ofan attack when anxiety from 7-8 of 10 to 4 of 10 seen. in 5 minutes. Therelief persisted. Patient liked it better than lorazepam. 14. 76 y/ofemale with Patient had MRI today with Xanax After 40 mg topical CBD,patient dementia since 2008. as pre-op for agitation. She was awoke andconversed with slumped over unresponsive as daughter-in-law. Dementiaresult. persisted but alerted from prior state. 15. 84 y/o female withMRI brain with numerous infarcts, Improved focus, attention and multiplestrokes and EEG with disorganized memory. More responsive and memoryproblems, background. Patient disoriented spontaneous. Prior leg painsand attentional issues. with poor memory. itching resolved as didautomatisms of picking her fingers. 16. 53 y/o female with Undergoingwork-up for seizures After 40 mg topical CBD, more confusion,unsteadiness, and Exam remarkable for unsteady gait calm and able towalk tandem, heaches. with inability to tandem, walk even with heels.Unable before heel-to-toe without falling to the with bare feet. right.Also anxious and jittery. 17. 66 y/o female with MRI brain with atrophy. . . EEG BP 145/80. After 40 mg topical memory problems and high withdisorganized background and CBD, 130/60. BP. frontal sharps. 18. 71 y/ofemale s/p stroke Spastic left hemiparesis with upper 10-15 minutesafter topical CBD, from AVM rupture 2 years extremity more affected.significant improvement in left ago. hand function: increased strengthand improved fine motor movements. 19. 55 y/o female s/p viral Anxiouswith burning neuropathic Reduced anxiety and less burning meningitis andcraniotomy pain of tongue and spasms of the pain and spasm of jaw. withseizures, neuropathic jaw/dystonia. pain, and anxiety. 20. 72 y/o femalewith 12 Fatigued, anxious, and with More alert and spontaneous with yr.Parkinson's disease with choreiform dyskinesias. marked reduction indyskinesias. multiple meds: Sinemet, Requip, Klonopin. 21. 27 y/o females/p auto Dizzy, tired, with neck spasm and Improved range of neck, moreaccident with certical sprain pain; visual convergence alert, andimprove visual and eye convergence difficulties. convergence. problems.22. 53 y/o female with MS Left spastic hemiparesis with Significantimprovement in left since 2002 on Copaxone, difficulty using hand andgait hemibody spasticity with better baclofen, recent steroids.problems. fine motor movements of hand and improved spastic gait in 10minutes after topical CBD. 23. 48 y/o female with Treatment with Vyvanse40 mg topical CBD had profound ADHD and anxiety. discontinued secondaryto effect on both anxiety and ADHD palpitations; Strattera did notsymptoms. work. Now with moderate anxiety and focusing problems. Smokingmarijuana daily for anxiety. 24. 61 y/o female with On Namenda, Abilify,Paxil, Dramatic improvement in affect dementia. Parkinson's apomorphine.with increased spontaneity, disease, paranoia, lethargy. improved gaitand general mobility. No change in memory but more responsive. 25. 80y/o male with On Lamictal, Risperdal, and More calm, less agitated, anddementia, impulsive Seroquel with agitation and improved thought processand behavior, agitation, anxiety. pressured speech, inappropriatespeech. comments. 26. 61 y/o female with Marked contracturing of rightarm Visibly improved right upper cerebral palsy, seizures, and and handwith spastic scissoring extremity function and gait. Also spastic righthemiparesis. gait. On Depakote, Tegretol, noted by her long termcaretaker. Valium, Rozerem, Remeron, and imipramine. 27. 72 y/o femalewith Disoriented, lethargic, with speech More alert, responsive anddementia, PD, hesitancy, and cognitive conversant. Tremors and gaithallucinations. dysfunction. Tremors of head and improved. hands. Rigidunstable gait. 28. 59 y/o female chronic Lethargic and mumbling speechMore alert, and responsive with encephalopathy and on Keppra, Lyrica,Mysoline, improved speech. seizures. Zonisamide. 29. 73 y/o female s/pExperiencing headache and neck Pain went to 3 of 10 in 15 accident withcervical disc pain, 8 of 10. minutes after topical CBD. herniation,headaches, seizures. 30. 80 y/o male with PD 5 On Sinemet, Azilect withanxiety After topical CBD, improved yrs. and tremors of mouth/chin andtremors and anxiety. hands. 31. 61 y/o female with MS Foggy, floatingfeelings with More clear and improved thought since 1999 on Tysabri.detachment from environment, “as process. when she smoked marijuana inthe remote past.” 32. 40 y/o female with Infantile affect and thoughtVisibly improved gait with arm cerebral palsy, chronic processes withsevere spastic swing, more communicative. encephalopathy, seizures,scissoring gait with no arm swing. and retardation.

EXAMPLE 6

The efficacy of a topical cannabidiol formulation was studied in a humanpatient (53 year old female s/p resection right clival meningioma)suffering from episodic severe post-operative neuralgic head painsuffering from severe right-sided neuralgic head pain every 15-20seconds. The patient was treated with cannabidiol 40 mg applied to theBONATH in a topical formulation. There was attenuation of associatedfocal EEG abnormalities. The EEG prior to treatment showed a righttemporal issue (disorganized slow sharp waves). After NUCHALadministration, her EEG showed attenuation of the right temporal wavesto a more normal state. The neuralgic head pain was less severe by about50% (frequency decreased to every 2-5 minutes). The EEG improvementlasted several minutes, but the clinical benefit lasted several hours.

EXAMPLE 7

The efficacy of a topical cannabidiol formulation was studied in a humanpatient having a remote head injury, s/p 4 craniotomies and intractableseizures. The patient was treated with cannabidiol 40 mg applied to theBONATH in a topical formulation. There was attenuation of associatedfocal EEG abnormalities. The EEG prior to treatment showed a rightfronto-central excessive beta and sharp waves. Post-treatment, the rightfast activity and sharp waves were attenuated. The right abnormalitieson the EEG were further attenuated after further topical nucal treatmentwith 25 mg milnacipran.

EXAMPLE 8

In Example 8, 34 patients having seizures, encephalopathy, and/orspasticity were treated with topical CBD at the back of the neck. Thetreatment comprised a dose of either 15 mg or 30 mg cannabinoid drugs,with the majority being CBD, the source of the CBD being CBD oilcommercially available from CannaVest. Table 2 below provides treatmentinformation and results.

TABLE 2  1. 9 y/o female with cerebral palsy, After one application ofCBD, spasticity seizures, and chronic encephalopathy. decreased by 80%within 15 minutes. Now on chronic use.  2. 73 y/o female withhydrocephalus, After application of CBD, improved gait with gaitdisorder, and anxiety; s/p VP shunt increased confidence and lessanxiety.  3. 21 y/o male with autism/Aspergers. After CBD, resolution ofracing thoughts, less Poor impulse control, racing thoughts, anxious andwith improved impulsivity. and anxiety Arrested for discharging gun in apharmacy trying to refill Xanax Rx.  4. 37 y/o male with mood disorder,impulse After CBD application, patient felt more and attentional issues,and memory focused, more relaxed and less agitated with problems. OnLamictal and Brintellix with reduced neck tension: felt he was in “slowsome control of behavior. motion” and not in usual activated state.  5.15 y/o male with autism; and poor After treatment with CBD, noticeablycalmer, impulse control, agitation, and outbursts. less reactive andimpulsive. On Lamictal and hydroxyzine.  6. 76 y/o female with MS,trigeminal Improved thought processes and mental neuralgia,encephalopathy, and confusion. state within 10 minutes.  7. 8 y/o femalewith complex partial More focused and calmer after CBD. Prior seizures,attention deficit disorder. abnormal EEG improved. Lamictal discontinuedas response to CBD was superior; now on daily use CBD.  8. 7 y/o malewith absence/petit mal On chronic use of topical CBD 2x/day withseizures with episodes of detachment, drop resolution of seizureepisodes. attacks and falls. MRI brain shows a thalamic hamartoma.  9. 6y/o male with petit mal epilepsy Rx'd Initially started on topical CBD2x/day, now Ethosuximide/Zarontin with inattention once daily withimproved attention and and poor school performance, bed-wetting. focuswith objective improved school work noted by teachers (did not know hewas on CBD). Resolved enuresis. Never took Zarontin. 10. 72 y/o femalewith strokes from anti- After CBD, improved thought processes, lessphospholipid syndrome, concussion, anxious and with improved sense ofwell- encephalopathy, and anxiety. being. 11. 61 y/o female with MS,seizures, After CBD application, patient felt more in unsteadiness andgait problems with falls. control of her body with improved gait andDepression from disabilities. thought processes. She felt more positiveand hopeful for first time. 12. 21 y/o female with Aicardi syndrome,After treatment with CBD, noticably more intractable seizures,agitation, and lack of spontaneous, interactive, and talkative. socialinteraction. After 2 months use, seizure frequency reduced 60%. Priordoses of Lamicatal and Depakote reduced. 13. 21 y/o female with cerebralpalsy, Improved interaction with others, less mental retardation andchronic agitation, and decreased anxiety. Currently encephalopathy withanxiety and social using CBD 2x/day. isolation. 14. 61 y/o male withchronic Topical CBD made patient more coherent encephalopathy frompesticide poisoning, and appropriate, with reduced anxiety and adrenalinsufficiency, and seizures with agitation. agitation. 15. 61 y/o females/p intracranial aneurysm On chronic use of topical CBD, more focused,rupture with chronic encephalopathy and resolved dizziness and chronicheadaches. headaches. 16. 54 y/o female with severe MS with Severebaseline spasticity improved 70% quadriparesis and spasticity all 4after one treatment with topical CBD to back extremities; on Baclofen,Klonopin, and of neck. Now continuing daily therapy. narcotics for pain.17. 72 y/o female with MS and cervical After CBD, improved walking,lifting feet, myelopathy with gait disturbance. and standing more erect.Also with improved mood and significantly more talkative. 18. 21 y/omale with autism/Asperger's After CBD application, became relaxed in awith poor impulse control, inattention, and better mood, and lessimpulsive. mood disorder. 19. 74 y/o cervical injury with paralysis andAfter one treatment with CBD, reduction in spasticity all extremities,lower worse. On spasticity by 30% from baseline. high doses of Baclofen,Tizanidine, and Dantrolene for spastic contracturing pain. 20. 18 y/owith anxiety precipitated 3 minutes after topical CBD application,complex partial seizures on Tegretol. anxiety reduced over 30%. Will beusing daily with plans to reduce Tegretol dose. 21. 79 y/o female withneck pain, PTSD, and PTSD symptoms improved after CBD use anxiety.2x/day; neck pain and headaches reduced 80%. 22. 36 y/o female s/p autoaccident with On topical CBD 2x/day without further head injury andseizures. Persistent complex seizures and tapering off Topamax. partialseizures 3x/day with headaches, on Headaches also relieved. Topamax. 23.53 y/o female with MS of 10 years with 30% reduction in spasticity inall 4 severe spasticity and gait problems extremities after CBDapplication to back of neck. Will be using topical CBD 2x/day. 24. 79y/o female with 9 months of post-op After single dose of topical CBD toback of encephalopathy with amnestic dementia, neck, became alert, moresociable and inattention, social withdrawal. Intolerant of interactive,and increased awareness. Will Namenda for memory due to agitation. useCBD 2x/day. 25. 37 y/o male with cerebral palsy, After a dose of topicalCBD to back of neck, lethargy, decreased interaction and became morealert, less spastic, and responsiveness. interactive, with increasedmobility. Will use CBD 2x/day. 26. 77 y/o male s/p head injury and 30minutes after topical CBD to back of neck, intracranial hemorrhage withdizziness, patient noted “clear vision, improved unsteadiness, and“foggy” thinking. dizziness, and better able to walk” which lasted 8hours. Now on 3x/day. 27. 87 y/o female with spasticity, peripheralPatient was more alert and responsive after neuropathy, myoclonus, andrestless legs topical CBD treatment and walked better. with gaitdisorder. Prescribed 2x/day. 28. 60 y/o male s/p auto accident with headOne dose of topical CBD relieved anxiety and injury and seizures, ADHD,neck pain for focus problems 80% and also relieved neck surgery,bi-polar disorder came in with pain ~50%. Patient will use CBD 2x/day insevere anxiety after traumatic deposition addition to the Namenda,Vyvanse, Vimpat, with attorneys. and Abilify. 29. 66 y/o female with MSand gait After one dose of topical CBD to the neck, disturbance onBaclofen and patient's stride improved: faster and more Mirapex.Symptoms began in 20's. smooth without prior hesitancy, shuffling andstiff leg character. 30. 78 y/o female with extensive strokes of 15minutes after application of topical CBD the cerebral hemispheres andbrainstem to the neck, gait visibly improved: less wide- with 3 years ofgait problems, now requiring based, picking up her feet, and moresmooth. a walker. Improvement noted by patient and several otherobservers. 31. 79 y/o female with MS, peripheral After one dose oftopical CBD to the neck, neuropathy and gait disorder. patient's gaitbecame more brisk and smooth, with less hesitancy on turns. 32. 47 y/omale s/p closed head injury with After a dose of topical CBD to the backof the seizures, concentration problems, and neck, became more relaxedand able to focus anxiety. better. Neck tension also resolved. 33. 56y/o male s/p head injury with post- 10 minutes after topical CBD to backof neck, concussive syndrome and PTSD: agitation more calm and focusedand at ease for the and poor concentration/focus. first time in a while.34. 40 y/o male with neonatal hypoxia, After topical CBD application toneck, attentional problems, seizures/cortical sensation of “white noise”distracting him irritability, insomnia. decreased and felt more focused.Will be using it 2x/day.

EXAMPLE 9

In Example 9, 13 patients having headaches and neck pain were treatedwith topical CBD at the back of the neck. The treatment comprised a doseof either 15 mg or 30 mg cannabinoid drugs, with the majority being CBD,the source of the CBD being CBD oil commercially available fromCannaVest. Table 3 below provides treatment information and results.

TABLE 3  1. 45 y/o female s/p auto accident with Chronic daily headachesresolved after daily intractable headaches and neck pain. Chronic CBDcream use. Remains headache free and migraines since high school.discontinued CBD.  2. 69 y/o female with head injury and subduralHeadaches and neck pain improved 30% with hematoma with severe headachesand neck CBD cream to neck. pain.  3. 73 y/o female with occipitalneuralgia and All pain symptoms resolved after 3 weeks of trigeminalneuralgia of 3 years duration. daily CBD use.  4. 23 y/o female withlong-standing severe 50% reduction in pain and improved mobility TMJpain. after CBD application to the TMJ and back of neck.  5. 60 y/ofemale with 3 months of continuous After one treatment with CBD,headache pain headaches, getting no relief with chronic diminished 50%for the first time. Prescribed narcotic use, topical CBD to the back ofneck 3x/day.  6. 24 y/o female with chronic headaches, s/p Withinseveral minutes of topical CBD sinus surgeries, and attentionalproblems. Daily application to back of neck, headache relieved headachesfor 10 years. over 40%; mother noted her eyes were brighter and she wasless tense. After week of daily use, headache free days for first timein 10 years.  7. 70 y/o male s/p head injury with post- 5 minutes aftertopical CBD to back of neck, concussive syndrome, PTSD, neck pain andreduction in head and neck pain by 50% with headaches; on regular usehydromorhone and reduced size of knot in neck. Also, more calm,hydrocodone. Used CBD mist in past. less anxious, and breathing easier. 8. 39 y/o female s/p auto accident with head Headache and neck painresolved 5-10 minutes injury, headaches, neck pain, and cognitive aftertopical CBD. Patient continues with problems. 2x/day use.  9. 48 y/omale with 10 days of right Bell's After CBD application to back of neckand palsy and pain in back of neck. Finished 2 region of stylomastoidforamen, right facial courses of oral steroids. weakness and decreasedsensation improved 30%. Neck pain resolved. 10. 89 y/o female s/p autoaccident with head Has been using topical CBD to the neck 1- and neckinjury with persistent neck pain with 2x/day with benefit for past 2months. Injury right arm pain and weakness. was over 2 years ago. 11. 78y/o female RN s/p fall 1 yr. ago with 5 minutes after topical CBDapplication to persistent neck pain and decreased ROM the neck, painresolve and ROM improved neck to the right. MRI shows spinal stenosis80%. Will continue to use daily. and severe spondylosis. 12. 51 y/ofemale with chronic headaches, On 2 occasions of severe headache,previously on narcotics and pain pump. PTSD used topical CBD applicationto the and mood disorder. neck; with pain going from 8 to 2 of 10 andfrom 8 to 3 within 15 minutes. Now using regularly. 13. 46 y/o femalewith 2 months daily One dose of topical CBD relieved headaches and neckpain. MRI brain consistent chronic headache and improved range withpseudotumor cerebri. of motion of neck. 14. 54 y/o female s/p autoaccident with Chronic back pain improved 30% concussion and back injury3 years ago. MRI within 15 minutes after topical CBD shows lumbar discherniation. application to the lower back. 15. 41 y/o female with acuteback pain with Pain resolved after several radiation into thigh fromlifting injury. treatments with topical CBD to the back. 16. 62 y/ofemale with 2 years of severe Thoracic pain reduced 30% withinpost-herpetic neuralgia/shingles. 10 minutes of topical CBD applicationto the thoracic spin in distribution of the pain.

EXAMPLE 10

In Example 10, 16 patients having back/spine pain, fibromyalgia, and/orextremity pain were treated with topical CBD at the back of the neck.The treatment comprised a dose of either 15 mg or 30 mg cannabinoiddrugs, with the majority being CBD, the source of the CBD being CBD oilcommercially available from CannaVest. Table 4 below provides treatmentinformation and results.

TABLE 4  1. 63 y/o female with fibromyalgia, chronic Now off narcoticsand on topical CBD to the back pain on narcotics. back of neck and back3x/day; pain relief within 2 minutes of application.  2. 79 y/o femalewith fibromyalgia, peripheral Pain relief lasts several days aftersingle neuropathy, and lumbar radiculopathy. applications of topicalCBD.  3. 80 y/o female with cervical radiculopathy 50% reduction in painin 5 minutes. and chronic neck pain.  4. 28 y/o female with 2 years ofthoracic pain. 60% reduction in chronic pain within a few minutes; nowusing daily.  5. Cervical and lumbar degenerative disc After onetreatment with CBD, decreased pain disease with left arm and leg painwith poor allowed patient to walk better and stand more posture. erect. 6. 52 y/o male s/p shoulder surgery on Within several minutes oftopical CBD narcotics with persistent pain and immobility application toshoulder and back of neck, pain of shoulder. diminished 40% withimproved mobility.  7. 74 y/o male with rheumatoid arthritis, 30-40%knee pain relief in 5 minutes. peripheral neuropathy, and knee painafter surgery.  8. 38 y/o male with right hand numbness and Right handsymptoms improved after topical tingling, seizures CBD.  9. 46 y/ofemale with persistent right knee pain. Significant relief in knee painwithin several minutes. 10. 29 y/o male with 3 month history of 6 of 10left lower extremity pain reduced to intractable back and left leg pain,minimally 2/10 after 10 minutes with improved strength responsive tosteroid dose-pack. Has been in left leg. unable to sleep as result ofaching leg pain. 11. 73 y/o female with long history of Topical CBD tothe lower back provided pain fibromyalgia, back pain, and peripheralrelief better than Tramadol. neuropathy on Tramadol and Lyrica. 12. 73y/o male with lumbar spinal stenosis and Topical CBD to the lower backresulted in neurogenic claudication. improved mobility and back painrelief within 10 minutes. 13. 59 y/o female with 2 weeks of neck painWithin 15 minutes of topical CBD application and immobility turning neckto right. MRI to neck, improved range of motion and shows severeosteoarthritis of C1-2. diminished pain. 14. 54 y/o female s/p autoaccident with Chronic back pain improved 30% within 15 concussion andback injury 3 years ago. MRI minutes after topical CBD application tothe shows lumbar disc herniation. lower back. 15. 41 y/o female withacute back pain with Pain resolved after several treatments withradiation into thigh from lifting injury. topical CBD to the back. 16.62 y/o female with 2 years of severe post- Thoracic pain reduced 30%within 10 minutes herpetic neuralgia/shingles. of topical CBDapplication to the thoracic spine in distribution of the pain.

EXAMPLE 11

In Example 11, 6 patients having Parkinson's disease, tremors, ormovement disorders were treated with topical CBD at the back of theneck. The treatment comprised a dose of either 15 mg or 30 mgcannabinoid drugs, with the majority being CBD, the source of the CBDbeing CBD oil commercially available from CannaVest. Table 5 belowprovides treatment information and results.

TABLE 5 1. 74 y/o female with long-term Parkinson's On topical CBD3x/day, 50% decrease in and tremors. tremors with less anxiety. 2. 42y/o female 4 yrs. Intractable left hemi- Facial twitching improved after5 minutes; now facial spasms s/p numerous Botox injections using 3x/day.and different meds. 3. 68 y/o male with long history of Tremors improved50% after 2 months use. familial/essential tremors. 4. 78 y/o female RNwith life-long head Head tremors improved 80% in 15 minutes tremorsunresponsive to prior therapies after one application of topical CBD toback of neck. Will use daily. 5. 77 y/o male, retired dentist withtremors, Handwriting sample and alertness improved 10 memory loss, andstrokes. minutes after topical CBD 3% application to the back of neck.6. 85 y/o male with strokes and Parkinson's 10 minutes after topical CBDapplication to the disease with gait problems. On Sinemet and back ofneck, visible improvement in fluidity Azilect. of gait with resolvedfestination/small steppage.

EXAMPLE 12

In Example 12, 19 patients having acute and chronic neurological andpsychiatric conditions were treated with topical CBD at the back of theneck. The treatment comprised a dose of either 15 mg or 30 mgcannabinoid drugs, with the majority being CBD, the source of the CBDbeing CBD crystalline powder oil commercially available from CannaVest.Table 6 below provides treatment information and results.

TABLE 6  1. 65y/o male with chronic neck, back, and leg After oneapplication of 1% CBD to neck and pain on narcotics. back, pain inprevious areas decreased additional 30% from prior baseline.  2. 62 y/ofemale with anxiety and mood After application of 1% CBD to back ofneck, disorder. visibly improved mood and less anxiety. Became “giggly.” 3. 78 y/o male with lumbar degenerative disc After application of 1%CBD to lower back, disease with left leg weakness improved strength ofleft leg and resolved back pain.  4. 28 y/o female with post-concussive1% CBD application to back of neck improved syndrome, with lethargy,cognitive dysfunction EEG disorganization and patient became more andabnormal EEG. alert and spontaneous.  5. 55 y/o male s/p remote strokewith spastic Within several minutes of 1% topical CBD right hemiparesisand expressive aphasia. application to back of neck and right forearm,spasticity improved with better movement of affected extremity.  6. 24y/o female with neck and back pain. Pain and pressure went down 50%within 1 minute of applying 1% topical CBD to neck and back.  7. 61 y/ofemale with long history of neck and 1% CBD application to back of neckimproved back pain, headaches on narcotics and using pain within threeminutes. Stated worked better 3% oil-based CBD topical cream. thanoil-based CBD she had been using.  8. 29 y/o male with anxiety and leftshoulder 1% topical CBD to neck and left shoulder pain, smokes marijuanadaily for relief of reduced anxiety and decreased shoulder symptoms.pain 20% within a few minutes.  9. 81 y/o female with cognitivedysfunction Applied 0.75% topical CBD to neck and1% to and back pain.back with patient feeling more alert and responsive, back paindiminished. 10. 20 y/o male with frontal head injury, 1.5% powderedtopical CBD cream had more agitation, and hallucinations of oil-basedCBD pronounced effect on anxiety and agitation. topical cream, Lamictal.11. 24 y/o female s/p auto accident with neck 1.5% topical CBD reducedneck tension and tension and pain. pain, improved range of motion. 12.72 y/o female with severe back and lower 2% topical CBD cream to lowerback relieved extremity neuropathic pain. back and lower extremityneuropathic pain. 13. 80 y/o female with Parkinson's disease and 1%topical CBD applied to back of neck tremors of head and left upperextremity. resulted in less anxiety, reduced tremors and improved gaitwith arm swing. 14. 87 y/o female with cervical spondylosis, Topical CBD1% to back of neck improved tremors of left hand. range of motion andreduced tremors. 15. 56 y/o male s/p head injury with cognitive 1%topical CBD to neck resulted in improved problems, focus issues, moodswings. focus, clearer thinking, and reduced anxiety. 16. 84 y/o femalewith multi-infarct state, 1% topical CBD cream to back of neck dementia,and agitation with anxiety. improved agitation and patient became morecooperative. 17. 42 y/o female with neck tension, pain, and 2% topicalCBD cream to back of neck headaches. relieved neck pain and tension from8 of 10 to 2 in few minutes. 18. 58 y/o female s/p numerous facialplastic 1.5% topical CBD cream to the left eye brow surgeries withneuropathic pain over left eye and back of neck reduced anxiety andrelieved brow. neuropathic pain. Had been using oil based CBD cream. 19.67 y/o female with strokes, s/p concussion, Had been using 3% topicaloil-based CBD with anxiety and cognitive problems. cream. 1.5% powderedCBD cream further relieved anxiety and improved demeanor.

EXAMPLE 13

In Example 13, 6 year old male suffering from a cerebellar posteriorfossa cyst, generalized seizure manifesting as standing and staring andunresponsive was treating in accordance with the present invention. FIG.2 is an EEG showing a baseline EEG of the patient of Example 13. Itrevealed findings consistent with absent seizures, i.e., three persecond spike and slow wave with generalized complexes. Previously,ethosuximide had been recommended for treatment, but the parents werereluctant to have the patient on a systemic convulsant therapy in viewof the potential side effects. The patient was treated with a 2% CBDcream to the nuchal (back of the neck) region twice a day. After twoweeks, the dosage regimen was changed to one application per day.

At the two week check-up, the patient was bright, awake, alert, orientedand nonfocal. The doctor was told that the patient was no long bedwetting, and significant improvement was noted by the patient's teachers(who had not been told that he was on a medication). His reading levelshad increased two levels, and he was more focused and paying attentionand his homework time was much easier. No seizures were noted.

FIG. 3 is an EEG showing an EEG post-treatment (i.e., after applicationof a topical unit dose of cannabinoid drugs) of the patient of Example13 at 5 minutes after the start of therapy. It showed attenuated seizurefocus. FIG. 4 is an EEG showing the EEG post-treatment (i.e., afterapplication of a topical unit dose of cannabinoid drugs) of the patientof Example 13 at 8 minutes after the start of therapy. It showed afurther attenuation of seizure focus as compared to the EEG shown inFIG. 3.

EXAMPLE 14

In Example 14, a 24 year old male patient had a head injury at age 14when he was run over by a truck. He presented with seizures (intractablecomplex partial seizures with secondary generalization; episodes ofencephalopathy for 24 hours thereafter). As shown in FIG. 5, an EEGtaken at initial examination (treatment with Vimpat and Onfi/clobazamonly) showed right fronto-central excessive beta and sharp waves. He hadhad 5 craniotomies, and previously had been treated with Dilantin,Carbatrol, Keppra, Lamictal, and Depakote. His current medications wereVimpat and Onfi (clobazam).

The patient was treated with 1 g of 1.6% CBD cream to the nuchal (backof the neck) region twice a day. At his one year follow-up examination,the patient was seizure-free. A follow-up EEG taken at that time (FIG.6) post-treatment with the 16 mg nuchal topical CBD administration twicedaily showed right fast activity and sharp waves attenuated. Thefollow-up EEG showed improvement: he was no longer showing seizurepotential. The patient remained on Vimpat, and his dose of Onfi wasreduced by half. At the time of patent filing, the patient was oncontinuous use of topical CBD for 20 months and remained seizure-freesince June 2014.

EXAMPLE 15

In Example 15, a 16 year old male patient presented with autism andgeneralized seizures. He was uncontrolled on Lamictal, Depakote, Keppra,Zonegran, ethosuximide/Zarontin. When examined, he presented withseizures about every 2 weeks on Banzel, Onfi, and Topamax asantiepileptics. FIG. 7 is a baseline EEG taken at the initialexamination, showing seizure focus, showing generalized slowing anddisorganization with left frontal sharp waves and paroxysms of sharpwaves and spikes.

The patient was treated with 1 g of 2% CBD cream to the nuchal (back ofthe neck). Within one minute of CBD application, there was improvementin the EEG background without previous burst activity (see FIG. 8, whichshows right fast activity and sharp waves attenuated). Clinically, thepatient became more alert and interactive. He continued therapy with thetopical CBD cream to the nuchal region twice daily, and the Topamax wastapered off, resulting in added overall improved encephalopathy. Seizurefrequency also was reduced, but the patient still had behavioral issuesremaining.

EXAMPLE 16

In Example 16, a 67 year old male patient presented with stroke andfocal seizures. autism and generalized seizures. FIG. 9 is a baselineEEG taken at the initial examination, showing left fronto-centralseizure focus.

The patient was treated with 1 g of 1.6% CBD cream to the nuchal (backof the neck). An EEG was re-taken 10 minutes after application of theCBD dose, and showed attenuated seizure focus (FIG. 10). The patientremains seizure free about 9 months after initiation of twice a day CBDtreatment to the nuchal region, which is also helping his spasticweakness from the stroke. He was able to return to work as abeterinarian and do surgery, which was unexpected as his Rehab MD hadpreviously advised him that we would have to retire.

EXAMPLE 17

In Example 17, a 7 year old male patient presented with atonic seizures.The patient would suddenly freeze and fall down (e.g., riding a bike, atschool, etc.). FIG. 11 is a baseline EEG taken at the initialexamination, showing cortical irritability on the left central regionc/w potential for seizures.

The patient was treated with 1 g of 1.6% CBD cream to the nuchal (backof the neck). An EEG was re-taken 10 minutes after application of theCBD dose, and showed attenuated seizure focus. FIG. 13 is a brain MRI ofthe patient showing a left thalamic hamartoma, a benign developmentalprocess, likely irritating the brain and causing his seizures. Thepatient has been seizure-free since initiating topical CBD therapy inthe nuchal region in October 2015 and is only on CBD as a mediation forhis seizures.

EXAMPLE 18

In Example 18, 19 patients having a variety of conditions were treatedwith topical CBD as set forth in Table 7 below. The CBD was compoundedin crystalline powder form rather than in CBD-oil form into the topicalcream. The doses were 7.5 mg (0.75% topical CBD cream), 10 mg (1%topical CBD cream), 15 mg (1.5% topical CBD cream) or 20 mg (2% topicalCBD cream).

TABLE 7 Patient/Condition Results  1. 65 y/o male with chronic neck,back, and leg After one application of 1% CBD to neck and pain onnarcotics. back, pain in previous areas decreased additional 30% fromprior baseline.  2. 62 y/o female with anxiety and mood Afterapplication of 1% CBD to back of neck, disorder. visibly improved moodand less anxiety. Became “giggly.”  3. 78 y/o male with lumbardegenerative disc After application of 1% CBD to lower back, diseasewith left leg weakness improved strength of left leg and resolved backpain.  4. 28 y/o female with post-concussive 1% CBD application to backof neck improved syndrome, with lethargy, cognitive dysfunction EEGdisorganization and patient became more and abnormal EEG. alert andspontaneous.  5. 55 y/o male s/p remote stroke with spastic Withinseveral minutes of 1% topical CBD right hemiparesis and expressiveaphasia. application to back of neck and right forearm, spasticityimproved with better movement of affected extremity.  6. 24 y/o femalewith neck and back pain. Pain and pressure went down 50% within 1 minuteof applying 1% topical CBD to neck and back.  7. 61 y/o female with longhistory of neck and 1% CBD application to back of neck improved backpain, headaches on narcotics and using pain within three minutes. Statedworked better 3% oil-based CBD topical cream. than oil-based CBD she hadbeen using.  8. 29 y/o male with anxiety and left shoulder 1% topicalCBD to neck and left shoulder pain, smokes marijuana daily for relief ofreduced anxiety and decreased shoulder pain symptoms. 20% within a fewminutes.  9. 81 y/o female with cognitive dysfunction Applied 0.75%topical CBD to neck and1% to and back pain. back with patient feelingmore alert and responsive, back pain diminished. 10. 20 y/o male withfrontal head injury, 1.5% powdered topical CBD cream had more agitation,and hallucinations of oil-based CBD pronounced effect on anxiety andagitation. topical cream, Lamictal. 11. 24 y/o female s/p auto accidentwith neck 1.5% topical CBD reduced neck tension and tension and pain.pain, improved range of motion. 12. 72 y/o female with severe back andlower 2% topical CBD cream to lower back relieved extremity neuropathicpain. back and lower extremity neuropathic pain. 13. 80 y/o female withParkinson's disease 1% topical CBD applied to back of neck and tremorsof head and left upper extremity. resulted in less anxiety, reducedtremors and improved gait with arm swing. 14. 87 y/o female withcervical spondylosis, topical CBD 1% to back of neck improved tremors ofleft hand. range of motion and reduced tremors. 15. 56 y/o male s/p headinjury with cognitive 1% topical CBD to neck resulted in improvedproblems, focus issues, mood swings. focus, clearer thinking, andreduced anxiety. 16. 84 y/o female with multi-infarct state, 1% topicalCBD cream to back of neck dementia, and agitation with anxiety. improvedagitation and patient became more cooperative. 17. 42 y/o female withneck tension, pain, and 2% topical CBD cream to back of neck headaches.relieved neck pain and tension from 8 of 10 to 2 in few minutes. 18. 58y/o female s/p numerous facial plastic 1.5% topical CBD cream to theleft eye brow surgeries with neuropathic pain over left eye and back ofneck reduced anxiety and relieved brow. neuropathic pain. Had been usingoil based CBD cream. 19. 67 y/o female with strokes, s/p concussion, Hadbeen using 3% topical oil-based CBD with anxiety and cognitive problems.cream. 1.5% powdered CBD cream further relieved anxiety and improveddemeanor.

EXAMPLE 19

Several combinations of CBD and traditional compounds were formulatedfor topical therapy. These combinations are outlined below using either2% or 3% CBD, made with 99.5% pure hemp-derived CBD.

The formula for 60 gram batch of 3% CBDerm is: CBD crystals 1.8 grams,Glycerine 3 ml, Liposomal base QS 60 grams. The formula for 60 grambatch of 2% CBDerm is: CBD crystals 1.2 grams, Glycerine 3 ml, Liposomalbase QS 60 grams.

The above 2% and 3% CBD products are combined with traditionally usedpharmaceutical compounds to produce the following:

-   2% CBD+5 mg melatonin for insomnia.-   2% CBD+Apomorphine 2 mg for Parkinson's disease, tremors, dystonia.-   2% CBD+10 mg phentermine for ADD/ADHD and Tourette's.-   2% CBD+25 mg milnacipran (Savella®) for anxiety & panic attacks,    mood disorders.-   2% CBD+4-AP (4-amino pyridine) 5 mg for DPN & other peripheral    neuropathic conditions.-   2% CBD+4-AP 5 mg+apomorphine 2 mg for spasticity and spasms.-   2% CBD+sumatriptan 25 mg+\−tizanidine 5 mg (optional active    ingredient) for migraine, tension headache.

Results:

The following 14 examples demonstrate the enhanced therapeutic effectexperienced when topical CBD is added to topical traditionalpharmaceutical compounds, or vice versa.

68 y/o male with MS spasticity, weakness, and cognitive slowing onlong-term topical 4-amino pyridine. When topical CBD added to 4-AP,reported thinking more clearly, more focused, improved fluidity of gait,and “overall feeling better.”

94 y/o male with Parkinson's disease, peripheral neuropathy, and gaitproblems on topical apomorphine. When CBD added to regimen, walkingimproved and moving more smoothly.

78 y/o female with tremors and chronic headaches on topical apomorphine.With the addition of topical CBD to the topical drug regimen, tremorsimproved with improved handwriting; headaches also resolved.

69 y/o female with tremors and left arm weakness on topical apomorphine.Adding topical CBD to apomorphine cream improved left arm strength andalleviated tremors.

64 y/o female with MS and spasticity of 4-amino pyridine topical cream,experienced improved spasticity and gait with addition of topical CBD to4-AP.

67 y/o female with MS and spasticity on 4-amino pyridine topical cream,walked more smoothly with combination with 3% CBD topical cream.

77 y/o male with diabetic neuropathy and pain on combination of 4-aminopyridine, methyl cobalamin, methyl folate, and 5-pyridoxal phosphate forsome time, experienced 80% additional improvement in pain andneuropathic symptoms with adding 3% CBD to topical regimen.

69 y/o male with familial tremors stable on long term regimen of topicalapomorphine, tremors improved slightly more with addition of topicalCBD.

44 y/o female s/p cervical fusion and neck pain on narcotics long term,with CBD 3% and apomorphine combination, had improved range of motion ofneck with additional reduction in pain.

78 y/o female with neck pain, with combination topical cream of 3% CBDand apomorphine, had improved neck movement with less spasm.

54 y/o female with thoracic disc protrusion and transverse myelitis, hadimprovement in lower extremity spasticity, sensory symptoms, anddecreased thoracic pain after using CBD and 4-amino pyridinecombination.

70 y/o male with head injury, PTSD, cervical fusion, and gait disorder,had been on 3% CBD cream for number of months. With addition ofapomorphine to the topical formula, he had improved sense of well-being,improved gait, and decreased neck pain and headache. He will be usingthe combination topical cream on a regular basis twice daily to the backof neck, “BON.”

79 y/o female s/p strokes with dementia, failed back syndrome, and gaitdisturbance, had been using topical CBD for pain applied to neck andback. With

-   4-amino pyridine added to added to topical preparation, the patient    experienced more alertness, spontaneity, and improved gait. She is    now using the combination CBD and 4-AP topical cream going forward.

50 y/o female with ADHD, impulsivity, chronic migraines, experiencedsignificantly improved ability to focus and being more calm and relaxedwith combination topical cream of CBD and phentermine.

In view of positive results noted with topical combinations of thecannabinoid CBD with other traditional neuro-active compounds, variouscombinations were made available to patients for their medicalconditions. The following chronic use combinations have been used inaccordance with the present invention, administered topically at theback of the neck:

-   3% CBD and 5 mg melatonin for insomnia: 11 patients;-   3% CBD and 2 mg apomorphine for spasticity, muscle spasm, tremor and    Parkinson's disease: 2 patients;-   3% CBD and 5 mg 4-aminopyridine for stroke, MS, demyelinating    disorders, and peripheral neuropathy: 13 patients;-   3% CBD and 25 mg sumatriptan for migraine attacks: 1 patient;-   3% CBD and 25 mg minacipran for seizures with anxiety and panic    attacks: 2 patients; and-   3% CBD and 10 mg phentermine for ADD/ADHD: 2 patients.

From the foregoing, it is apparent a synergistic therapeutic processoccurs when a cannabinoid, such as CBD, is combined to a traditionalpharmaceutical agent and the topical combination used to treat a medicalcondition. Whether this occurs only with the method of the presentinvention because of its unique nature of action through cell surfacereceptors on cutaneous free nerve-endings is not known at this time.With systemic drug deliveries, widespread dispersion and activation ofdrugs through the blood may not be conducive to a synergistic effect. Onthe contrary, systemic drug-drug interactions and side effects mayoccur.

At this point, it is unclear whether observed enhanced therapeuticefficacy is on the basis of cannabinoids enhancing specific functions oftraditional compounds, such as neurotransmitter release and binding; theresult of extraneous actions attributable only to cannabinoids; or, acombination of both processes. In light of the fact that cannabinoidsexert many other therapeutic influences than influencingneurotransmitter release and binding, it is likely that the explanationwill be it is a combined effect. It is clear, however, that the methoddescribed herein of topical administration of a Cannabinoid(s) alongwith a second therapeutically active agent provides an additionalpowerful treatment option for several difficult neurological andneuropsychiatric conditions. It should also be noted this enhancement oftherapeutic benefits through combining of a traditional pharmacologicagent with CBD (or other cannabinoid) is different from “EntourageEffect,” which is combining various ratios of different cannabinoids(for example, CBD-THC combinations) to achieve different effects.

CONCLUSION

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

The active agents may be incorporated into the topical formulations intherapeutically equivalent amounts. The actual dose of an active agent(relative potency) may be determined based on a comparative dose to atherapeutically effective dose of an active agent described herein.However, it is noted that the differences in oral doses may not directlycorrespond to the differences in doses that are therapeuticallyeffective via transdermal delivery of the serotonin agonist. Factorssuch as metabolism of the serotonin agonist, the ability of the drug topass through the skin, among others, may affect the amount of serotoninagonist necessary to provide a therapeutic effect. One skilled in theart would readily understand this and adjust for the same.

The hypotheses of the inventor provided throughout the specification arefor possible explanation purposes only, and are not meant to be limitingin any way.

1. A method of treating a disease state or condition in human,comprising topically applying onto the surface of the skin in an areaextending from behind one ear to the other ear of the mammal and belowthe hairline at the back of the neck of a human patient a unit dose of acannabinoid drug(s) and a second therapeutically active drug intherapeutically effective amounts formulated in a mousse, cream, gel orointment that allows for the drug to be immediately absorbable andavailable for the free nerve endings of the trigeminal nervous systemwhich reside under the skin surface to treat the disease state orcondition to the back of the neck region of a human patient to provideregional neuro-affective therapy to the human patient.
 2. (canceled) 3.The method of claim 1, wherein the cannabinoid drug(s) and the secondtherapeutically active drug are administered such that they are absorbedin an area at or above the skin where the afferent components oftrigeminal nerve system, cervical sympathetic nerves, and vagus nerveare located.
 4. (canceled)
 5. The method of claim 4, wherein thecannabinoid drug(s) is administered in a topical pharmaceuticalformulation at the back of the neck at the hairline of the humanpatient.
 6. (canceled)
 7. The method of claim 1, wherein the cannabinoiddrug(s) comprise a mixture of pharmaceutically acceptable cannabinoids,such that the mixture provides substantially no psychoactive effect orno psychoactive effect.
 8. The method of claim 1, wherein thecannabinoid drug(s) comprises at least about 80% cannabidiol.
 9. Themethod of claim 1, wherein the topical pharmaceutical formulationcomprises a pharmaceutically acceptable aqueous based carrier.
 10. Themethod of claim 9, wherein the cannabinoid drug(s) in the pharmaceuticalformulation comprises at least about 80% cannabidiol.
 11. (canceled) 12.(canceled)
 13. (canceled)
 14. The method of claim 1, wherein the thesecond therapeutically active drug is a dopamine agonist.
 15. The methodof claim 1, wherein the condition is selected from the group consistingof benign essential/familial tremor, tremor related to MS, chronicencepahalopathies such as from stroke or head injuries, congenital CNSdegeneration conditions/cerebral palsy, cerebellar degenerationsyndromes, and spasticity conditions and the second therapeuticallyactive drug is a dopamine agonist.
 16. The method of claim 1, whereinthe condition is Parkinson's Disease and the second therapeuticallyactive drug is a dopamine agonist.
 17. (canceled)
 18. The method ofclaim 1, further comprising a third therapeutically active drug which isa skeletal muscle relaxant.
 19. The method of claim 18, wherein the theskeletal muscle relaxant is tizanidine.
 20. (canceled)
 21. The method ofclaim 1, wherein the cannabinoid drug(s) comprises cannabidiol.
 22. Themethod of claim 10, wherein the aqueous based pharmaceuticallyacceptable carrier comprises Ethoxydiglycol, Water (Aqua), Glycerin,C₁₂₋₁₅Alkyl Benzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol,Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, Magnesium AluminumSilicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate(Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil,Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil,Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin CPalmitate), Pro-Lipo Multi-emulsion Liposomic System, Tetrasodium EDTA,Phenoxyethanol, and Sodium Hydroxymethylglycinate.
 23. The method ofclaim 8, wherein cannabidiol is incorporated into the pharmaceuticallyacceptable carrier from a CBD—oil.
 24. The method of claim 8, whereincannabidiol incorporated into the pharmaceutically acceptable carrier isa purified crystalline CBD.
 25. The method of claim 1, wherein the unitdose comprises from about 3 mg to about 50 mg cannabidiol.
 26. Themethod of claim 8, wherein the unit dose comprises from about 3 mg toabout 50 mg cannabidiol.
 27. The method of claim 14, wherein the unitdoses comprises from about 0.25 mg to about 4 mg of the dopamineagonist.
 28. The method of claim 27, wherein the unit doses comprisesfrom about 2 apomorphine.